吡咯并喹啉醌(PQQ)的生命史: 一种对生命系统产生新影响的多功能分子

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The life history of pyrroloquinoline quinone (pqq): a versatile molecule with novel impacts on living systems

Abstract

摘要

Pyrroloquinoline quinone (PQQ) acting as redox cofactor of Glucose dehydrogenase is orthocyclic antioxidant acting under multifarious environmental stress and rich conditions in prokaryotes as well as eukaryotes. Microbes are the exclusive source of PQQ biosynthesis and for biocatalysis of glucose into gluconic acid and 2-ketogluconic acid by gram positive and negative bacteria. This study focus to describe PQQ biography (1979-2016) highlighted its applications acts as biocatalyst by enhanced production of NADH from pqqC, involved in several important mechanisms like bacterial energy transduction by m-ATPase, production of biocontrol substances, growth stimulating activities and DNA repair. PQQ acting as anti-neurological, anti-degenerative, anti-melanogenic and anti-cancer agent due to its antioxidant nature by scavenging free radicals. PQQ is modulator of immunity by CD4 cells count and IL-2, sleep maintenance by PGC-1 alpha pathway and inflammation due to ROS. The mineral phosphate solubilization results in plant growth promotional, biocontrol, antifungal and ISR activities. PQQ nanoparticles used for production of Biofuels cells and sulfonated polymers. It acts as a modulator of diverse signaling pathways like STAT, MAPK, JAK, JNK, P13K/Akt, mTOR, EGFR and Raps for cell proliferation, differentiation, apoptosis, Box translocation and metabolic pathways by phosphorylation of ADP and suppression of reactive oxygen species. It protects from oxidative stress by acting as Alpha AA modulator of lysine metabolism, TrxR1 in selenium metabolism, low density lipoprotein in lipid metabolism, ATP production in Energy, Glucose and carbohydrate metabolism. It has been structurally characterized with bioinformatics tools and future perspectives being molecular modeling and docking for analytical drug design.

吡咯并喹啉醌(PQQ)作为葡萄糖脱氢酶的氧化还原辅助因子,是原核生物和真核生物中在多种环境胁迫和丰富条件下发挥作用的一种正环状抗氧化剂。微生物是 PQQ 生物合成的唯一来源,也是革兰氏阳性菌和阴性菌催化葡萄糖生成葡萄糖酸和2- 酮葡萄糖酸的唯一来源。介绍了 PQQ 传记(1979-2016)的研究进展,重点阐述了 pqqC 产生的 NADH 在生物催化方面的应用,它参与了细菌间质 atp 酶能量转导、生物控制物质产生、促生长活性和 DNA 修复等重要机制。PQQ 具有清除自由基的抗氧化作用,具有抗神经系统、抗退化、抗黑色素生成和抗癌作用。PQQ 通过 CD4细胞计数和 IL-2调节免疫,通过 PGC-1α 途径维持睡眠,调节 ROS 引起的炎症反应。无机磷的溶解作用促进了植物的生长、生物防治、抗真菌和 ISR 活性。PQQ 纳米粒子用于生产生物燃料电池和磺化聚合物。它通过磷酸化 ADP 和抑制活性氧类蛋白的表达,作为 STAT、 MAPK、 JAK、 JNK、 P13K/Akt、 mTOR、 EGFR 和 Raps 等多种信号通路的调节剂,调控细胞增殖、分化、凋亡、 Box 转位和代谢途径。它通过作为赖氨酸代谢的 α AA 调节剂,硒代谢中的 TrxR1,脂质代谢中的低密度脂蛋白,能量、葡萄糖和糖代谢中的 ATP 产生来保护人体。利用生物信息学工具对其进行了结构表征,并展望了分析药物设计的分子模拟和对接技术的发展前景。

Keywords: life history, pyrroloquinoline quinine, novel biomolecule, living systems, microorganism, plants and animals

关键词: 生活史,吡咯喹啉喹啉,新生物分子,生命系统,微生物,植物和动物

Introduction

引言

Pyrroloquinoline quinone (4, 5-dihydro(4), 5-dioxo(1)H-pyrroloquinoline-2,7, 9 tricarboxylic acid) being a three ortho cyclic quinone substitutes the role of a redox-cofactor for various bacterial dehydrogenases such as methanol, ethanol and glucose dehydrogenases1‒6 also termed as methotaxin.7 PQQ structure prediction shows that it has been originated from tyrosine and Glutamic-acid8 but the pathway for PQQ biosynthesis is whist in process of identification.9 PQQ being involved in Gluconic acid production and biosynthesis by microbes. GDH-A and GDH-B (s-GDH) are soluble enzymes.10 PQQ synthesizing operon containing 6-7 genes i.e. (pqqABCDEF/G)11,12 and orientation effects13 and biocatalysis are carried by bioelectric oxidation of glucose into gluconic acid.14 It acts as potent microbial growth stimulant and diversified role in antibiotics as chief biological control determinant for plant pathogens.15 PQQ-GDH has role in direct electron transfer of bacterial energy transduction and ATP synthesis during oxidation.16,17 The soluble membrane bound serine and threonine kinases repair damage of DNA by radiation.18 PQQ has diverse roles in animals like NMDA mediated receptor in neurological injury, repair and improved memory by ERK1/2 pathway pathway.19 PQQ is a powerful anti-melanogenic agent and quite effective against disorders related to hyper pigmentation.20 It plays role in MAPk kinase activation and tyrosyl phosphorylation of ERK2 by production of CD4+ T lymphocytes.21 PQQ promotes and improves neonatal development and reproduction involving mitochondrial biogenesis and cell signaling pathways.22 PQQ plays vital role in liver fibrogensis23 and in signal transduction via mitochondrial biogenesis.24 It has diverse functions in insulin resistance and aging by creation of new mitochondria.25

吡咯并喹啉醌(4,5-二氢(4) ,5-二氧(1) h- 吡咯喹啉-2,7,9-三元羧酸)是一种3邻苯二酚类化合物,取代了氧化还原辅因子对各种脱氢酶的作用,如甲醇、乙醇和葡萄糖脱氢酶1-6也称为甲氧嘧啶。GDH-A 和 GDH-B (s-GDH)是可溶性酶。10 PQQ 合成含有6-7个基因的操纵子。(pqabcdef/g)11,12和取向效应13和生物催化由葡萄糖生物电氧化成葡萄糖酸。14它在抗生素中作为强有力的微生物生长促进剂和多样化作用,是植物病原菌的主要生物防治决定因子。15 PQQ-GDH 在细菌能量转导和氧化过程中 ATP 合成的直接电子转移中起作用。可溶性膜结合丝氨酸和苏氨酸激酶修复辐射对 DNA 的损伤。18 PQQ 通过 ERK1/2途径在 NMDA 介导的受体等动物神经损伤、修复和记忆改善中发挥多种作用。19 PQQ 是一种强有力的抗黑色素生成剂,对色素沉着相关疾病非常有效。20它通过产生 CD4 + t 淋巴细胞参与 MAPk 激酶的活化和 ERK2的酪氨酸磷酸化。21 PQQ 通过线粒体生物合成和细胞信号通路促进和改善新生儿发育和生殖。22 PQQ 通过线粒体生物合成在肝纤维化23和信号转导中起重要作用。24它通过产生新的线粒体,在胰岛素抵抗和衰老中发挥多种作用。图25

In plants PQQ has phosphate solubilizing activities, plant growth promotion, antifungal activities, induces systematic resistance and symbiosis by acting as an antioxidant.26‒28 In modern era of technology PQQ has been extensively used in bio-electrocatalysis, nanotechnology and polymer based technologies.29‒31 In this review we have focused upon bioinformatics based structural analysis of PQQ-GDH having propeller’ fold superbarrel made up of 8-sheet `propeller blades’ with tryptophan docking motifs.32 Five transmembrane segments in N-terminal region while C-terminal region having a huge binding domain for PQQ conserved with functions related to catalytic center.30 The oxidation of D-glucose to D-gluconate by m-GDH is catalyzed by Pseudomonas & Gluconobacter.33 PQQ on c-terminal being conserved in Alcohol dehydrogenase of Pseudomonas putida have same ontology.30There are ciprocityin acetic acid bacteria for ethanol resistance PQQ-ADH.34 The mGDH appears to be unique in mechanism of PQQ-binding with bivalent metal ions by steady continuous production of gluconolactone.35 The mechanism of docking involves activator ammonia with its unique cytochromes.36

PQQ 在植物体内具有解磷活性、促进植物生长、抗真菌活性、诱导系统抗性和作为抗氧化剂的共生作用。在现代技术时代,PQQ 已广泛应用于生物电催化、纳米技术和聚合物基技术。29-31在这篇综述中,我们着重于基于生物信息学的 PQQ-GDH 螺旋桨的结构分析,该螺旋桨的超级桶由带有色氨酸对接图案的8片“螺旋桨叶片”组成。32 PQQ 的 n 端有5个跨膜片段,c 端有一个巨大的结合域,与 PQQ 的催化中心有关。30假单胞菌和葡萄糖酸杆菌催化 m-GDH 氧化 d- 葡萄糖生成 d- 葡萄糖酸酯。33pqq 在 c 终端上保存在醇脱氢酶恋臭假单孢菌中,具有相同的本体。30对乙醇耐药的细菌有西普罗西汀和醋酸菌。34连续稳定生产葡萄糖酸内酯的 mGDH 与二价金属离子的 pqq 结合机制似乎是独特的。35分子对接机理涉及活化剂氨及其独特的细胞色素。图36

The S-GDh has catalytic potential, adduct-forming ability, reversible substrate binding, direct transfer of a H and oxidation of PQQH2 by an electron acceptor.37 It makes headway via undivulged pathway that requiring six genes, pqqC to –F, pqqC as rate controlling gene38 and supply energy for growth on alcohol or aldoses substrates.39The biochemical pathways, physiological, cellular and molecular processes involving PQQ are linked to metabolic pathways for protection against oxidative stress by scavenging Reactive oxygen species(ROS).

该基因具有催化潜力、加成物形成能力、可逆底物结合能力、 h-的直接转移能力和 PQQH2被电子受体氧化能力。37该基因通过6个基因(pqqC to-f,pqqC 作为速率控制基因38,pqqC 作为在乙醇或醛类底物上生长的能量)的未知途径取得进展。39涉及 PQQ 的生化途径、生理、细胞和分子过程与代谢途径相关,可通过清除活性氧(ROS)来保护氧化应激。

PQQ role in microbes

PQQ 在微生物中的作用

Sources of PQQ

PQQ 的来源

PQQ as catalytic center of gram negative bacteria,40 discovered in 1979 acting as redox agent.41 Many bacteria comprehend the genes required for PQQ biosynthesis like Klebsiella pneumonia and Acinetobacter calcoaceticus, but Salmonella typhimurium and Escherichia coli are not able to synthesize PQQ (Figure 1), because they lack genes encoding them.42,43 The obtained nucleotide and protein sequence from Escherichia adecarboxylata, E. adecarboxylata, reclassified as Leclercia adecarboxylatahomology of 99% of ECloacae subsp. with Enterobacteriaceae by extrication of glucose dehydrogenase.30 GDH-A has been reported in numerous bacterial species like Klebsiella aerogenes, Escherichia coli P. Ae ruginosa, G. Suboxydans, Acinetobacter calcoaceticus, and A. Lwoffi while s-GDH found in A. Calcoaceticus. PQQ is scarcely present animal and plant tissues, could not be produced by plants and animals. Produced in plant-associated systems by rhizobacterial source.44PQQ is important growth cofactor the techniques and methodologies should be more clearly defined for extraction of its bioactive form.

许多细菌理解 PQQ 生物合成所需的基因如肺炎克雷伯菌和钙酸不动杆菌,但是鼠伤寒沙门氏菌和大肠桿菌不能合成 PQQ (图1) ,因为它们缺乏编码它们的基因。30gdh-a 已在多种细菌中发现,如产气克雷伯氏菌(Klebsiella aerogenes)、肠道细菌、钙酸不动杆菌(Acinetobacter Calcoaceticus)和大肠桿菌(a. Lwoffi) ,而 s-GDH 则在钙酸不动杆菌(a. Calcoaceticus)中发现。PQQ 几乎不存在动植物组织,不可能由动植物产生。PQQ 是重要的生长辅因子,提取其生物活性物质的技术和方法应更加明确。Figure 1 图1Different bacteria producing gluconic acid by oxidation of glucose and other end product. 不同细菌通过氧化葡萄糖等终产物产生葡萄糖酸11

PQQ biosynthesis

PQQ 生物合成

The K. Pneumonia is an excellent host microorganism for PQQGDH-B production(Kojima et al.2000).The gene pqqA in bacteria conceal 23-29 amino acids, pqqC being highly conserved in K. Pneumoniae 23 amino acids (Figure 2),45,46 PqqA is 20 folds larger than the PqqC or PqqE.47 The aldehydes, ketones and organic acids are excreted by gluconobacter sp, being catalyzed by dehydrogenases in periplasmic space.48 The pqqC gene with 29 kDa molecular weight (250 residues) acts as catalystfor synthesis of PQQ49 (Figure 3) compressed into hydrophobic helix bundle49 of 90 residues in pqqD.50 The pqqDGCBA in Methyl bacterium strain being distinguished by complementation resolution, pqq-FAB of K. Pneumoniaesequence analysis51 showed 11 genes (A-B-C-D-E-F-H-I-J-K and M) present in PQQ-operon of P. Fluorescens were recognized.52 The PQQ operon of G. Oxydans contains pqqABCDEF53,54 and pqqABCDEF in 621H gene of G. Oxydans.55 The structural characterization shows that PqqC is important for catalyzing the reaction, PqqD for production of PQQ, PqqD for interaction and PqqE for cluster formation while a functional characterization is required for PQQ biosynthetic process to be involved in various biological processes.

肺炎是产生 pqgdh-b 的优良宿主微生物(小岛等人,2000)。细菌中的 pqqA 基因含有23-29个氨基酸,肺炎克雷伯菌中的 pqqC 高度保守(图2) ,45,46 pqqA 比 pqqC 或 PqqE 大20倍。47. 周质空间的脱氢酶催化葡萄糖酸杆菌分泌醛、酮和有机酸。48分子量为29kda (250个)的 pqqC 基因对 pqqq49的合成起催化作用(图3) ,在 pqd 中,pqqC 基因被压缩成90个氨基酸残基的疏水螺旋束。通过互补分离鉴定 Methyl 细菌 pqqDGCBA 基因,肺炎克雷伯菌 pqq-FAB 分析显示11个基因(A-B-C-D-E-F-H-I-J-K 和 m)存在于荧光克雷伯菌 PQQ-operon 基因中。52氧丹 g. Oxydans 的 PQQ 操纵子含有氧丹 g. Oxydans 621H 基因的 pqqABCDEF53、54和 pqqABCDEF。55. 结构角色塑造表明 PqqC 对于催化反应很重要,PQQ 的 pqd 对于生成 PQQ 很重要,pqd 对于相互作用很重要,PqqE 对于团簇的形成很重要,而 PQQ 的生物合成过程需要一个功能角色塑造来参与各种生物过程。

PQQ as biocatalyst

生物催化剂 PQQFigure 2 图2(A) pqqABCDEF, the PQQ genome. 3 (B) PQQ formation by cross linking of tyrosine & Glutamate. (a) pqqABCDEF,PQQ 基因组。3(b) PQQ 是由酪氨酸和谷氨酸交联而成76Figure 3 图3The relationship between coenzyme PQQ biosynthesis protein B and its biosynthetic protein. 辅酶 PQQ 合成蛋白 b 与其生物合成蛋白的关系

PQQ acts as a potent biocatalyst the fact is proved by the reaction rate at 11,800 presuming biologically active structure due to oxidation of glucose in bioelectrocatalytic way (Figure 4).56 (PQQ)-dependent (GDH) acting as electron sink57 and NADPH enhancing the production of PQQ by PqqC-D, product inhibition.58 The endogenous PQQ genes in K. Pneumoniae along with heterologous expression in Escherichia coli were over expressed in T7 promoter.59 PQQ being enzymatic biocatalyst is involved in many-oxidation reduction processes can be used for production of many biocatalytic products of industrial significance.

PQQ 作为一种强有力的生物催化剂,在11,800的反应速率证明了这一事实,假定葡萄糖以生物电催化的方式氧化为生物活性结构(图4)。56(PQQ)依赖型(GDH)作为电子 sink57和 NADPH 促进 pqc-d 产生 PQQ,产物。58 k. ae 的内源 PQQ 抑制基因和异源 PQQ 表达于 T7启动子。59 PQQ 是一种酶促生物催化剂,参与了多种氧化还原过程,可用于许多具有工业意义的生物催化产品的生产。Figure 4 图4The Gluconic acid production from Glucose. 葡萄糖制备葡萄糖酸的研究181

PQQ as microbial growth stimulant

微生物生长促进剂

PQQ has growth stimulating effect by decrease of the lag period and subsequently increasing growth speed, yield and induction of cell reproduction60 by subsequent growth increase at the exponential phase acting assecondary type of growth stimulant (Figure 5).61,62 PQQ acts as a growth factor for many bacteria under stress and normal conditions63 and also reported for growth stimulating activities by formation of growth stimulating factors, apoqunioproteins by free PQQ and adduct.64 The biologically active PQQ found in periplasmic spaces is known to be growth stimulant and isolation of cofactor containing active site can lead to elevated production of PQQ.

PQQ 具有生长刺激作用,通过减少滞后期,随后增加生长速度、产量,并通过指数期的生长增加诱导细胞繁殖60(图5)。 PQQ 作为一种生长因子,对许多细菌在应激和正常条件下生长,63并且报道了生长刺激因子、游离 PQQ 和增生剂形成的 apoqunioproteins 的生长刺激活性。64在血浆周围空间发现的生物活性 PQQ 被认为是生长刺激剂,含有活性位点的共同因子的分离可以提高 PQQ 的生长。Figure 5 图5Diagrammatic pathway to show mechanism of PQQ acting as biostimulant/micro booster. PQQ 作为生物兴奋剂/微型助推器作用机制的图解途径

PQQ role in antibiotics

PQQ 在抗生素中的作用

The antibiotics phenazine, 1-carboxylic acid and 2,4-diacetylphloroglucinol are used as bio-control determinants of Pseudomonas spp65 providing unequivocal evidence that antibiotics have a role in the suppression of disease.66 Six pqq genes and one GDh gene has been identified in R. Aquatilis strains, found necessary for biosynthesis of the Antibacterial substqnceABS, as biocontrol of crown gall disease.67 The (GDHm) is a 86 kDa68 double mutants of PQQ are more sensitive and ndvB stimulates antibiotic resistance by sequestration of drugs in cyclic glucans and ethanol oxidation genes activates antibiotic resistance (Figure 6).69 PQQ can suppress damping-off caused by the oomycete by genes (sup 5&6) for biocontrol activities (Table 1),70 An associated cytochrome c approaching the PQQ for direct electron transfer.71 The Pseudomonas putida’s being chloramphenicol resistant bacterium is involved in metabolism, cellular regulation and stress with gene regulation by efflux transporters and biosynthesis of proteins.72 The physiological roles played by PQQ for regulation of intracellular polyamines and other perspective should be genetically worked out for production of antibiotics.

抗生素吩嗪、1- 羧酸和2,4-二乙酰基间苯三酚被用作假单胞菌 spp65的生物控制决定因子,提供了明确的证据证明抗生素有抑制疾病的作用。66在水瓶菌株中鉴定出6个 pqq 基因和1个 GDh 基因,发现这些基因是生物防治冠瘿病所必需的。GDHm 是 PQQ 的一个86kda68双突变体,它更敏感,ndvB 通过在环状葡聚糖中螯合药物而刺激抗生素抗药性,而乙醇氧化基因则激活抗生素抗药性。69 PQQ 可以抑制卵菌基因(sup 5和 sup 6)引起的阻尼现象,用于生物防治活动(表1) ,70一个相关的细胞色素 c 接近 PQQ 直接作用于电子转移。71. 恋臭假单孢菌耐氯霉素细菌通过外排转运体和蛋白质的生物合成参与代谢、细胞调控和胁迫的基因调控。72 PQQ 在调节细胞内多胺方面的生理作用以及其他生产抗生素方面的前景值得从遗传学角度研究。

Gene基因Size大小Function功能Reference参考资料
PqqEM. extorquens敲诈勒索384Biofilm-specific antibiotic resistance, ΔndvB, biocontrol activities at logarithmic phase生物膜特异性抗生素抗药性,ndvb,对数生物防治活性47, 484748
PqqBM. extorquens勒索299Same biocontrol and antibiotic resistance functions like PQQE同样的生物控制和抗生素抗药性功能,就像 PQQE45, 6845,68
PqqCA. calcoaceticu石灰酸钙252Biofilm,antibioticresistance,biocontrol like PQQB生物膜,抗菌性,生物控制,如 PQQB54, 67,42546742
PqqD, R. aquatilis水族箱85Requires NADH , O2, biocontrol activities at logarithmic phase需要 NADH,O2,生物防治活动在对数阶段29图29
pqqF Klebsiella pneumoniae克雷伯氏肺炎菌资历架构83,616 Da83616 DaAntibiotics pyoluteorin (Plt) and 2,4-diacetylphloroglucinol (Phl) production for disease suppression为抑制疾病而生产的抗生素吡咯替林(Plt)和2,4-二乙酰基间苯三酚(Phl)26,282628

Table 1 Antibiotic and biocontrol activities of PQQ operon

表1 PQQ 操纵子的抗生素和生物防治活性Figure 6 图6Microarray analysis of ethanol oxidation genes in 乙醇氧化相关基因芯片分析P. Aeruginosa 铜绿假单胞菌and ndvB genes. 和 ndvB 基因

PQQ in bacterial energy transduction

细菌能量转导中的 PQQ

PQQ-GDH from A. Calcoaceticus and glucose oxidase from A. Nigar with cytochrome b(562) as electron acceptor in transfer of oxidoreductases,the quaternary structure of which do not have transfer subunit for electrons (Figure 7).73 Biologically active energy being conserved NADH2oxidations during the periplasmic oxidation of PQQH2.74 Two forms of metabolic energy can be inter-connected by the action of ion-translocating ATPases.75 PQQ is involved for modification and oxidation by cell signaling acting as a Redox cofactor and powerful antioxidant.76,77 A pronounced insight should be made on pathways related energy production due to attribution of PQQ on mitochondrial functions and ATPase production.

细胞色素 b (562)作为电子受体转移氧化还原酶,其四级结构中没有电子转移亚基(图7)。在 PQQH2的周质氧化过程中,nadh2氧化产生的生物活性能。两种形式的代谢能可以通过离子转运 atp 酶的作用相互联系。75 PQQ 作为氧化还原辅助因子和强抗氧化剂参与细胞信号转导的修饰和氧化。76,77由于 PQQ 在线粒体功能和 atp 酶产生方面的属性,应该对与能量产生有关的途径有明确的认识。Figure 7 图7Bacterial energy transduction. 细菌能量转导

ATP synthesis during oxidation

氧化过程中 ATP 的合成

PQQ/PQQH2 oxidation-reduction involved in transfer of electrons to electron acceptors by reckon on the specific quinoprotein enzyme, cytochrome c(Cu-protein), NADH dehydrogenase and cytochrome b.78 Glucose being tremendous energy generation substance for transport of secondary solutes in PQQ-GDH a powerful role in energy metabolism(Figure 8)(Figure 9).79 PQQ-dependent production of gluconic acid by Acinetobacter, Agrobacterium and Rhizobium species. PQQ enhances energy production (ATP) by protecting existing colossal mitochondrial biogenesis and high number of m-dehydrogenases (Figure 10).80 2PQQ catalyzes the oxidation of thiol groups perilously allied with the function of two proteins, i.e. thioredoxin and phosphoribulose kinase in catalysis and stabilization of protein structure.81

PQQ/PQQH2氧化还原参与电子转移到电子受体的过程,依赖于特定的藜蛋白酶、细胞色素 c (Cu-protein)、 NADH脱氢酶和细胞色素 b. 78葡萄糖是 PQQ-GDH 中次生溶质运输的巨大能量产生物质,在能量代谢中起着强大的作用(图8)。PQQ 通过保护已有的大量线粒体生物合成和高数量的 m 脱氢酶(图10)来增强能量产生(ATP)。802pqq 催化巯基的氧化,与硫氧还蛋白和磷酸丁糖激酶两种蛋白质的功能密切相关Figure 8 图8The m, PQQ- and FAD- dehydrogenases in acetic-acid bacteria (outer surface). 乙酸菌的 m、 PQQ-和 FAD 脱氢酶(外表面)1Figure 9 图9(A) The E. coli cells with YfgL and PQQ synthase in protein profile of plasmid71 (B)PqqE disruption and cell survival as response to different doses of g radiation. (a)在不同剂量 g 辐射下,具有 YfgL 和 PQQ 合成酶的大肠杆菌胞浆71(b) PqqE 破裂蛋白谱及细胞存活139Figure 10 图10(a) PQQ causing inhibitory effect for formation of fibril amyloid β21 (b) Evaluation of different PQQ concentrations on the bEND.3 cells. (a) PQQ 对淀粉样原纤维形成的抑制作用(b)不同浓度 PQQ 对 bEND. 3细胞的影响102

PQQ intracellular signaling in DNA repair

PQQ 在 DNA 修复中的细胞内信号转导

Oxidation of lipids, proteins, and nucleic acids hinder membrane function and integrity, inactivation of enzymes, modification of lipoproteins, and chemical alteration of DNA.82 PQQ for m-bound soluble kinases like serine-threonine involved in repair of radiation induced DNA damage, repair and recombination by strong interaction of yfgL mutant wihaving wild recA genes through a cell signaling (Figure 11).83 In DNA end resection requirement for CDK1, DNA damage checkpoint activation for homologous recombination provides evidence for PQQ for induction process in repair of DNA by kinase protein as radiation resistant substance.84 PQQ synthesis manifests sensitivity to gamma rays, double break in DNA helix, repair of STK domain (eukaryotes and prokaryote).85 The pqqD is essential for PQQ biosynthesis in K. Pneumonia.86 PQQ-dependent sugar dehydrogenase gene with auxiliary activities and structural hallmarks provides distinctive penetration into the mechanism of oxidation by metabolism pathway of sugars.87 PQQ with its metal ions, NADH mediated functions and transcription factors can lead to repair of DNA cleavage sites.

脂类、蛋白质和核酸的氧化阻碍了膜的功能和完整性,酶的失活,脂蛋白的修饰和 DNA 的化学改变。82 PQQ 为 m 结合的可溶性激酶,如丝氨酸-苏氨酸,通过细胞信号通路与含有野生 recA 基因的 yfgL 突变体强相互作用参与修复辐射引起的 DNA 损伤、修复和重组(图11)。83在 CDK1的 DNA 末端切除要求中,同源重组的 DNA 损伤检查点激活为 PQQ 诱导过程中激酶蛋白作为抗辐射物质修复 DNA 提供了证据。84 PQQ 合成对 γ 射线敏感,DNA 螺旋双断裂,STK 结构域(真核生物和原核生物)修复。85 pqd 在 k 肺炎 PQQ 生物合成中起重要作用。86 pqq 依赖性糖脱氢酶基因具有辅助活性和结构特征,通过糖代谢途径对氧化机制有独特的渗透作用。87 PQQ 及其金属离子、 NADH 介导的功能和转录因子可导致 DNA 切割位点的修复。Figure 11 图11PQQ supplementation on scores of sleep performance (A) sleepiness and awakening (B) sleep start and retain (C) Nightmare (D) Fatigue recovery (E) sleep time frame(F) Effects of PQQ supplementation on sleep. PQQ 对睡眠成绩的影响(a)嗜睡和觉醒(b)睡眠开始和保持(c)噩梦(d)疲劳恢复(e)睡眠时间框架(f) PQQ 对睡眠的影响109

PQQ role in animals

PQQ 在动物中的作用

PQQ in neurological injury and repair

PQQ 在神经损伤修复中的应用

The compilation of oxygen-imitative free radicals can oxidize the NMDA receptor acquired the degree of neuroprotection, inflammation and neurotoxicity due to excessive glutamate.88,89 Pyrroloquinoline quinone is an enhancer of nerve growth factor NGF production in vitro,90 not able to damage barrier between blood and brain enhancing activation of first NRF-1and second nuclear respiratory factor (NRF-2).91,92 PQQ inhibiting cytotoxicity of the alpha-synuclein variants and amyloid fibril formation and believed to be a strong candidate as a compound for treatment of PD (Figure 10),93Pyrroloquinoline quinone triggers ERK1/2 pathway, regulation of glutathione, modulation of Bcl-2 and Bax.94 PQQ impoverish pain sensation by protection against chronic neuropathy, sciatic nerve irritability and injury in animals was reduced with PQQ and enhanced sequential oxidative +3 stress by restoration of neurotransmitter levels in brain.95 PQQ acting as anti-neurodegenerative compound from glutamate damage96,97 by reversible action of middle artery occlusion98 affecting learning ability and memory function of rats model significantly.99 The disorders like Alzheimer’s, dementia and Parkinson’s disease, stroke, Huntington’s disease are neurodegenerative.100‒102 PQQ prevents accumulation of alpha-synuclein and amyloid beta proteins.103 PQQ provides advanced level of protection on endothelial cells of mouse brain from Gluco-damage by suppression of ROS and cell death by blocking signaling pathway of JNK.104‒107 The treatment of proliferated Schwann cells with various concentrations of PQQ enhanced the expression of CREB, c-fos, c-jun and PCNA.108 PQQ on traumatic brain injury (TBI) has found to be neuroprotective109 as measurements of physiological parameters indicated that PQQ restrains function of brain in older people related attention, working and memory.110 PQQ can act as a strong candidate to be used in pahrmacogenomics of brain injuries and other complications.

氧模拟自由基的形成可使 NMDA 受体获得谷氨酸过量所致的神经保护、炎症和神经毒性的程度。88,89吡咯并喹啉醌是神经生长因子 NGF 体外生产的增强剂,90不能破坏血脑屏障,增强第一核转录因子 -1和第二核呼吸因子(NRF-2)的激活。91,92 PQQ 抑制 α 突触核蛋白变体的细胞毒性和淀粉样纤维的形成,被认为是治疗帕金森病的一个强有力的候选化合物(图10) ,93吡咯并喹啉醌触发 ERK1/2通路,调节谷胱甘肽,调节 Bcl-2和 Bax。94 PQQ 对动物慢性神经病变、坐骨神经过敏性和损伤的保护作用使疼痛感减弱,通过恢复脑内神经递质水平增强连续性氧化 + 3应激。95 PQQ 作为谷氨酸损伤96,97的抗神经退行性化合物,通过中动脉闭塞可逆作用98对大鼠学习记忆功能有显著影响。99像阿尔茨海默氏症、痴呆症、帕金森氏症、中风、亨廷顿氏症这样的疾病都是神经退行性疾病。100-102 PQQ 阻止 α-突触核蛋白和 β 淀粉样蛋白的积累。103 PQQ 通过抑制活性氧和阻断 JNK 信号通路,对小鼠脑内皮细胞的 gluco 损伤提供高水平的保护作用。104-107不同浓度 PQQ 处理增殖的雪旺细胞,增加 CREB、 c-fos、 c-jun 和 PCNA 的表达。生理参数测定表明,PQQ 抑制老年人注意力、工作和记忆方面的大脑功能,发现 PQQ 对创伤性脑损伤有神经保护作用。110 PQQ 可以作为一个强有力的候选人,用于脑损伤和其他并发症的 pahrmacogenomics。

PQQ role in skin

PQQ 在皮肤中的作用

PQQ is anti-melanogenic agent as melanin is the consequential determinant of diverse hyper-pigmentation disorders, synthesized by various transcriptional factors, tyrosinase-related protein (TRP-1 and -2), and tyrosinase.111 Novel allyl PQQ combination with chlorogenic acid and methyl gentisate is found effective for hyper pigmentation acknowledged at diminution of skin hyper pigmentation (Gold; jhskincareclinic.co.uk).Loss of PQQ causes a reduction in connective tissue growth and repair proved by Cellular studies on fibroblasts leading to friable skin, loss of elasticity and connective tissue health also used in make-up and creams for aging and skin care etc. PQQ contributes on epidermal water dissipation, skin moisture, texture, viscoelasticity, and reduction in mast cell quantity in the dermis and epidermis and quantity of CD3⁺ T-cells giving improved skin barrier and function (Table 2).112 PQQ causing biological aging induced by ultraviolet A UVA in dermal fibroblasts of humans HDFs via ant apoptotic SIRT1- SIRT6-HO‑1 and Nrf2 signaling pathways.113 It protects against long wavelength UVA rays targetingretinoid and alpha hydroxy skin cells as an ingredient in most anti-aging creams. PQQ works on mitochondria involved in cell signaling, cycling, differentiation, and growth increase cellular turnover through exfoliation.114 The American Academy of Anti-Aging Medicine has published a book where PQQ has been enlisted as an ingredient for anti-aging because it preserves mitochondira, slows down hardening of arteries, replaces hormones with bioidentical one’s.115 Due to involvement of PQQ in lysine metabolism and pronounced effects on skin layers it can be a novel component in contribution with other skin compounds in health care industry.

PQQ 是一种抗黑色素生成剂,因为黑色素是由多种转录因子、酪氨酸酶相关蛋白(TRP-1和-2)和酪氨酸酶合成的多种超色素沉着障碍的决定因子。111新的烯丙基 PQQ 与绿原酸和龙胆酸甲酯的结合被认为对减少皮肤超色素沉着有效(Gold; jhskincareclinic.co.uk )。皮肤成纤维细胞的研究证实,PQQ 的缺失会导致结缔组织生长和修复的减少,从而导致皮肤脆弱、失去弹性和结缔组织健康,这些也被用于化妆品、老化霜和护肤品等。PQQ 通过细胞凋亡的 SIRT1-SIRT6-HO-1和 Nrf2信号通路,在人类皮肤细胞中引起由紫外线 a UVA 引起的衰老(生物)。PQQ 作用于参与细胞信号传递、循环、分化和生长的线粒体,通过脱落增加细胞周期。美国美国抗衰老医学科学院学会出版了一本书,其中 PQQ 被列为抗衰老的成分,因为它保存了丝裂素,减缓了动脉硬化,用生物相同的激素取代了激素。由于 PQQ 参与赖氨酸代谢并对皮肤层产生显著影响,它可以成为保健行业中与其他皮肤化合物一样的新成分。

Item项目Group组别Week 0第0周Week 4第四周Week 8第八周
Wrinkles皱纹Placebo安慰剂-0.9±0.7- 0.9 ± 0.7-0.1±0.2- 0.1 ± 0.2-0.5±0.5- 0.5 ± 0.5
PQQ-1.6±0.5- 1.6 ± 0.5-0.5±0.6**- 0.5 ± 0.6 *-0.6±0.7*- 0.6 ± 0.7
Pigmentation色素沉着Placebo安慰剂-2.3±0.6- 2.3 ± 0.6-1.4±0.4- 1.4 ± 0.4-0.5±0.6- 0.5 ± 0.6
PQQ-3.6±0.5- 3.6 ± 0.5-1.3±0.6*1.3 ± 0.6 *-0.7±0.6**- 0.7 ± 0.6

Table 2 Effect of PQQ intake on the subjective recognition on of facial skin conditions22

表2 PQQ 摄入量对面部皮肤状况主观认知的影响22

PQQ role in immunity

PQQ 在免疫中的作用

PQQ regulates MAPk kinase activation and tyrosyl phosphorylation of ERK2 by production of CD4+T lymphocytes116 having immune response by interleukin-2, and growth factors reduced when T-cell proliferation occurs.117 When PQQ supplemented orally in nano-amounts alleviates the mitogens of B and T cells.118 PQQ treatment enhances IgA level, restores mass of GALT119 and induce immunity against bacterial or viral invasion,120 subsequent suppression by increased levels of proteins induced by IFN-β via iNOS, JAK1 and STAT1 signaling pathways (Table 7). PQQ was involved in phosphorylation of 1KKβ, p38 and nF-kB as a pre-inflammatory retort of macrophages121 increase the number of lymphocytes and CD8+cells (Table 3).19 Robust research should be conducted on clinical trials to estimate IL-6 and T lymphocytes to act as immune-suppressive agent.

PQQ 通过产生具有白细胞介素 -2免疫应答的 CD4 + t tes116,调节 MAPk 激酶的激活和 ERK2的酪氨酸磷酸化,并在 t 细胞增殖时降低生长因子。117口服纳米量的 PQQ 可减轻 b 细胞和 t 细胞的丝裂原。118 PQQ 治疗可提高 IgA 水平,恢复 GALT119的数量,诱导对细菌侵袭或病毒侵袭的免疫反应,120随后通过 ifn- 诱导的蛋白质水平,通过 JAK1和 STAT1信号通路诱导的蛋白质水平增加(表7)。PQQ 参与1kk、 p38和 nF-kB 的磷酸化,作为巨噬细胞增加淋巴细胞和 CD8 + 细胞数量的预炎症反应(表3)。

Group组别ΑβTCR+Tcr +γδTCR+Tcr +CD4+4 +CD8+8 +
PP LymphocytesPP 淋巴细胞IG-STD-PNGb/t13749-1992 IG-STD-PN2.07 ±0.212.07 ± 0.210.10 ±0.020.10 ± 0.021.68 ±0.171.68 ± 0.170.49 ±0.080.49 ± 0.08
IG-PQQ-PN2.76 ±0.272.76 ± 0.270.12 ±0.010.12 ± 0.012.37 ±0.242.37 ± 0.240.47 ±0.040.47 ± 0.04
IE LymphocytesIE 淋巴细胞IG-STD-PNGb/t13749-1992 IG-STD-PN1.24 ±0.411.24 ± 0.410.24 ±0.050.24 ± 0.050.58 ±0.230.58 ± 0.230.94 ±0.020.94 ± 0.02
IG-PQQ-PN0.75 ±0.130.75 ± 0.130.22 ±0.060.22 ± 0.060.36 ±0.100.36 ± 0.100.65 ±0.120.65 ± 0.12
LP Lyphocytes脂蛋白淋巴细胞IG-STD-PNGb/t13749-1992 IG-STD-PN1.12 ±0.201.12 ± 0.200.28 ±0.060.28 ± 0.060.53 ±0.070.53 ± 0.071.05 ±0.221.05 ± 0.22
IG-PQQ-PN0.83 ±0.110.83 ± 0.110.27 ±0.050.27 ± 0.050.43 ±0.050.43 ± 0.050.72 ±0.100.72 ± 0.10

Table 3 Absolute lymphocyte numbers with added PQQ)120

表3添加 PQQ 后的淋巴细胞绝对数

PQQ link to oxidative stress, tolerance and sleep

链接到氧化应激,耐受性和睡眠

PQQ administration results in considerable improvements in span of sleep, improvements in total duration of sleep, avoid of awakenings at night but not for nightmares (Figure 11),122 being treated with 20mg PQQ for 8 weeks in 17persons.123 The insomnia might be attributed to fatigue and stress which are indirectly involved with oxidative stress and ROS. Oral administration of PQQ, zinc, vitamin E and coenzyme Q10 improves sleep quality and time period.124 Multiple studies should be carried out on persons with impaired sleep to show its correlation with normal sleep cycle.

服用 PQQ 可以显著改善睡眠时间,提高睡眠总时间,避免夜间醒来,但不能防止噩梦(图11) ,122名患者服用20毫克 PQQ 8周。123失眠可能是由于疲劳和压力引起的,而疲劳和压力间接与氧化应激和 ROS 有关。口服给药、锌、维生素 e 和辅酶 Q10可以提高睡眠质量和改善睡眠时间。

PQQ role in Inflammation and disease by free radicals

PQQ 在自由基引起的炎症和疾病中的作用

By PQQ optimization a marked reduction in quantitative degree C-reactive plasma protein and Il-6 various urietic markers of oxidative stress endowed consistent with mitochondria-related boosted functions.125 High levels of reactive oxygen species ROS is associated with cellular and mitochondrial damage causing inflammation leading to deteriorative disease126 as potential reformat to oxidative damage in PTU-induced mice kidney.127 Divergent circumstances related to inflammation, oxidative stress, and metabolic dysregulation by increasing mitochondrial biogenesis, enhanced inflammation, and to alleviate the level of endogenous enzymatic and non-enzymatic antioxidants in a subject (Table 4).31 PQQ in osteoarthritis OA can be investigated by the iNOS level execution of novel pharmacological and clinical prevention in the near future.21 In rheumatoid arthritis RA of anti-inflammatory effects of PQQ were interrogated in interleukin (Il)-1β MAP and JNK kinase pathways, hindered by PQQ in IL-1β of Sw982 cells , can be a promising therapeutic agent(Table 4).34 It critically constrains the creation of PGE2 and NO with suppression of COX-2, MIP-1a ,TNF-a, MCP-1 ,IL-1b, iNOS, IL-6, and LPS reacted with microglia as pro and pre-inflammatory mediators.22 Observational impact of PQQ on suppression of ROS and inflammatory effects can be used in prognosis and treatment of all major diseases.

通过 PQQ 优化,c 反应蛋白和 Il-6各种尿生成标志物的定量程度明显降低,这些氧化应激与线粒体相关的增强功能是一致的。高水平的活性氧类氧自由基与引起炎症的细胞和线粒体损伤相关,导致致病变恶化。通过增加线粒体生物合成,增强炎症,减轻内源性酶和非酶抗氧化剂的水平,与炎症、氧化应激和代谢失调有关的不同情况。31 PQQ 在骨性关节炎中的作用可以通过近期开展新药物和临床预防的 iNOS 水平来研究。21. 在 RA 类风湿性关节炎中,观察 PQQ 在白细胞介素 -1map 和 JNK 激酶通路中的抗炎作用,发现 PQQ 受到 Sw982细胞 Il-1中 PQQ 的阻断,可能是一种有前途的治疗药物(表4)。34通过抑制 COX-2、 MIP-1a、 tnf-α、 MCP-1、 IL-1b、 iNOS、 IL-6和 LPS 与小胶质细胞作为促炎和预炎介质,严重抑制 PGE2和 NO 的生成。22 PQQ 对活性氧抑制和炎症效应的观察作用可用于所有主要疾病的预后和治疗。

Control控制UHMWPE超高分子量聚乙烯UHMWPE+PQQ (1 mg/kg)Uhmwpe + pqq (1毫克/千克)UHMWPE+PQQ (10mg/kg)Uhmwpe + pqq (10mg/kg)
BMD (mg/cc)骨密度(毫克/毫升)24.452±1.64424.452 ± 1.6449.342±0.895*9.342 ± 0.895 *14.453±0.546*,@14.453 ± 0.546 *21.340±1.344#,∧,∇21.340 ± 1.344 # ,∧ ,something
BVF变频调速器14.423±0.90914.423 ± 0.9095.845±0.670*5.845 ± 0.670 *8.342±0.932#,@8.342 ± 0.932 #11.232±0.908#,∧,∇11.232 ± 0.908 # ,∧ ,something
CMT(mm)CMT (毫米)0.392±0.0140.392 ± 0.0140.150±0.021*0.150 ± 0.021 *0.301±0.019#,∧0.301 ± 0.019 # ∧0.365±0.023∧0.365 ± 0.023∧
Ca/Ta13.213±0.77813.213 ± 0.7786.431±0.509*6.431 ± 0.509 *8.423±0.783*8.423 ± 0.783 *11.807±0.813#,@,∇11.807 ± 0.813 # ,@

Table 4 Bone histomorphometry parameters after 14-day treatment with PQQ79

表4 PQQ79治疗14天后的骨组织形态计量学参数

PQQ as cancer fighter

作为抗癌战士的 PQQ

PQQ acquires the probability to forage ROS and inhibition of cell-apoptosis, the mechanism of which is related to oxidative accentuate by mitochondrial pathways, acting as a potential pharmaceutical agent.128 PQQ contributes to tumor cell apoptosis and death, deterioration in levels of ATP degree and disintegration of membrane potential of mitochondria, in affiliation with down commandment protein expression (Bcl-2), up-modulation of caspase-3 in activated form and MAPK levels of protein phosphorylation in interrupted state of expression.129 PQQ offers remarkable radiation protection for cancer patients receiving radiation treatment, acting as inhibitor of a pathway called mTOR causing tumor development and cancer cell proliferation.130 The activation of suppressor gene like p53 causing Bcl-2 transcription of Bax-X protein, p53 up regulated attune of PUMA for apoptosis and gene DJ-1 protected by oxidative stress.131The alliance of ROS with apoptosis via Bcl-2, mechanism of PQQ can be used in cancer related therapies.

PQQ 获得了搜寻活性氧和抑制细胞凋亡的可能性,其机制可能与线粒体途径的氧化加重有关,可能是一种潜在的药物。128 PQQ 与下调蛋白表达(Bcl-2)、活化型 caspase-3上调和中断表达状态下丝裂原活化蛋白激酶(MAPK)磷酸化水平相关,参与肿瘤细胞凋亡和死亡、 ATP 水平下降和线粒体膜电位解体。129 PQQ 为接受辐射治疗的癌症患者提供了显著的辐射防护,作为一种被称为 mTOR 的途径的抑制剂,可以导致肿瘤的发展和癌细胞的增殖。130抑癌基因如 p53的激活引起 Bax-X 蛋白 Bcl-2的转录,p53上调 PUMA 的凋亡调节,DJ-1基因受氧化应激保护。131 ROS 通过 Bcl-2与细胞凋亡的联合作用,PQQ 的作用机制可用于肿瘤相关治疗。

PQQ effects on cell growth

PQQ 对细胞生长的影响

PQQ was found competent initially at first growth phase but not at the exponential phase, hence identified as growth promoting substance, and essential nutrient.132‒134 The antioxidant nature of PQQ enables it to scavenge and generate superoxide vital for conventional growth proliferation and development.135 The fertility, birth and growth was decreased in absence of PQQ associated with decreased steady-state mRNA levels for procollagen Type-I α1-chains.136 PQQ promotes and improves neonatal development and reproduction involving mitochondrial biogenesis and cell signaling pathways.137 It can induce autophosphorylation of tyrosine in epidermal growth factor receptor EGFRPQQ provoked by Reactive oxygen species intracellular and activation of EGFR markedly hindered by antioxidants.138 When PQQ·Na2 was supplemented in the diet of broiler chicks they showed an increase in growth performance, carcass characteristics, biochemical parameters of plasms and breast muscle development.139 No fatality, mortality and toxicologically significantly alters body weight and necropsy related food utilization and organs.140 PQQ was proved to have no genotoxic effect on cells and activities141 providing more facts on the possible health endangerment by replicated exposure.142 The impairment of mitochondria and production of ROS have been correlated with pathological conditions accompanied by apoptosis.143

PQQ 在生长初期具有生长活性,但在指数生长阶段不具有生长活性,因此被确定为促生长物质和必需营养素。PQQ 的抗氧化特性使其能够清除并产生对常规生长增殖和发育至关重要的超氧化物。135没有 PQQ,生育力、出生率和生长率下降,i 型前胶原1- 链稳态 mRNA 水平下降。136 PQQ 通过线粒体生物合成和细胞信号通路促进和改善新生儿的发育和生殖。137它可以诱导细胞内由于细胞内的自体磷酸化活性氧类和抗氧化剂明显阻碍 EGFR 的活化而引起的表皮生长因子受体蛋白酪氨酸的升高。138肉仔鸡日粮中添加 PQQ Na2后,生长性能、胴体特性、质体生化指标和胸肌发育均有所提高。139病死率、死亡率和毒性无显著改变体重和尸检相关的食物利用和器官。140 PQQ 被证明对细胞和活动没有遗传毒性作用,提供了更多关于重复接触可能危害健康的事实。142线粒体损伤和活性氧产生与伴有细胞凋亡的病理状态有关。143

PQQ in liver fibrogensis

PQQ 在肝纤维化中的作用

PQQ intensify biliverdin evacuated from the liver via gallbladder due to decline of glucocorticoid as glutathione eliminating bile components.144 Inflammation of the gastrointestinal tract has strong association with ROS genesis. The treatment related to anti-fibrosis remained an unconquered era for drug progression, development.PQQ via scavenging activity can open new horizons in this field.145 A significant protection in liver and colon cells was found with administration of PQQ146 and to extricate untimely senescence, provoked by eradication of Bmi-1 and inhibition of oxidative stress by ROS can cause liver impairment.147 Multiple lines of evidence indicate that NOX-generated ROS engaged in crucial function of liver pathogenesis.148 A series of experiments should be carried out on clinical trials to show the relation of ALT levels and PQQ intake.

由于作为谷胱甘肽消除胆汁成分的糖皮质激素减少,PQQ 增强胆绿素经胆囊从肝脏排出。肠粘膜的炎症与 ROS 的产生有很强的关联。145 PQQ146对肝脏和结肠细胞具有显著的保护作用,并能提早衰老,这是由于 Bmi-1消失和 ROS 抑制氧化应激可导致肝脏损伤。

PQQ in signal transduction via mitochondrial biogenesis

通过线粒体生物合成研究信号转导中的 PQQ

The pathway of mitochondrial biogenesis in signal transduction executes the trigger of cAMP, CREB and PGC-1α (Figure 12).149 PQQ uses cell signaling pathways150 for many mitochondria-related functions having energy-related metabolism and the mechanism of action (Table 8).151 PQQ can enhance action of PGC-1α, which in turn contributes to proliferation of mitochondria and stabilization of membrane that happens by CREB phosphorylation.152 The genetic expression is being influenced by PQQ also acting as modulator of various pathways can play significant roles in biological processes.

149 PQQ 使用细胞信号通路150对许多线粒体相关功能进行能量相关的代谢和作用机制(表8)151 PQQ 可以增强 pgc-1的作用,这反过来又促进线粒体的增殖和 CREB 磷酸化所发生的膜的稳定。152 PQQ 的遗传表达受到 PQQ 的影响,也作为各种通路的调节器在生物过程中发挥重要作用。Figure 12 图12PQQ activates nuclear respiratory factors (NRF-1, NRF-2)), PQQ 激活呼吸细胞核因子(NRF-1,NRF-2) ,34

PQQ in cardiac disease

PQQ 在心脏病中的应用

PQQ consummate resistance for severe oxidative emphasis in mature rat cardiac cells by mechanism of motor-action in heart.153 PQQ acting as a free-radical forager and cardio protective, with reduced levels of myocardial tissue (MDA), a signal index of lipid-peroxidation.154 The PQQ confabulate protective effects on rat cardiomycetes by oxygen/glucose deprivation (OGD)-induced and PI3K/Akt pathway by inhibiting intracellular ROS levels.155 The plasma triacylglyceride, and β-hydroxybutryic acid accumulation were enhanced in PQQ deficient rats rather than PQQ containing rats and cardiac injury was more pronounced in (PQQ− rats) than in (PQQ+ rats) (Table 5).155 The pharmacological studies should be conducted for targeting PQQ as heart relaxant and therapeutic.

PQQ 通过心脏运动作用机制对成熟大鼠心肌细胞严重氧化损伤具有完善的抗性。153 PQQ 具有自由基代谢和心肌保护作用,降低心肌组织脂质过氧化信号指标 MDA 含量。154 PQQ 通过抑制细胞内 ROS 水平,对 OGD 诱导的大鼠心肌细胞和 PI3K/Akt 通路的保护作用进行了研究。155 PQQ 基因缺陷大鼠血浆三酰甘油和-羟基丁酸的积累较 PQQ 基因缺陷大鼠明显增加,PQQ 基因缺陷大鼠的心肌损伤明显大于 PQQ 基因缺陷大鼠(表5)。155应进行 PQQ 作为心脏松弛剂和治疗药物的药理学研究。

Lipid class1脂质类1Treatment治疗Total lipid2总脂肪2Fatty acid composition1脂肪酸组成1
SFA国家林业局MUFA单极射线发生器PUFA多不饱和脂肪酸N3N6N7N9DM糖尿病
Neutral lipids(nmol fatty acid per g sample)2中性脂质(每克样品中脂肪酸)2
Cholesterol Ester胆固醇酯PQQ+PQQ +1219±2681219 ± 268188±21188 ± 21114±22114 ± 22914±233914 ± 23315±3.415 ± 3.4899±231899 ± 23116±3.916 ± 3.998±1898 ± 180
PQQ-PQQ –1271±2341271 ± 234189±27189 ± 27103±19103 ± 19977±195977 ± 19513±3.613 ± 3.6963±192963 ± 19214±3.614 ± 3.689±1689 ± 160
PQQ+/-PQQ +/-1439±781439 ± 78199±23199 ± 2389†±7.189 ± 7.11149±591149 ± 5917±3.017 ± 3.01131±591131 ± 5914±1.914 ± 1.974†±9.074 ± 9.00
FFA11PQQ+PQQ +467±83467 ± 83196±44196 ± 4496±1696 ± 16175±25175 ± 258±3.78 ± 3.7166±22166 ± 2212±3.412 ± 3.482±1282 ± 120
PQQ-PQQ –508±55508 ± 55197**±41197 * * 41106±8.0106 ± 8.0203**±22203 * * 229±4.89 ± 4.8193**±23193 * * 2311±4.011 ± 4.093**±1193 * * 110
PQQ+/-PQQ +/-371±122371 ± 122148±40148 ± 4080±3080 ± 30143±52143 ± 527±2.47 ± 2.4136±50136 ± 5011±4.611 ± 4.666±2566 ± 250
Diacylglycerol二酰甘油酯PQQ+PQQ +59±9.859 ± 9.827±4.427 ± 4.415±3.615 ± 3.617±5.817 ± 5.80.7±0.60.7 ± 0.616±5.716 ± 5.71.8±0.71.8 ± 0.712.6±3.012.6 ± 3.00.5±0.80.5 ± 0.8
PQQ-PQQ –952695 * ± 263487.0348 * ± 7.0237.023 * ± 7.0351235 * ± 123.82.43.8 * ± 2.4311131 * ± 112.90.82.9 * ± 0.8206.320 * ± 6.31.9±1.61.9 ± 1.6
PQQ+/-PQQ +/-60±1360 ± 1321±1.721 ± 1.716±2.316 ± 2.323±9.423 ± 9.40.8±0.50.8 ± 0.522±9.022 ± 9.01.8±0.11.8 ± 0.114±2.414 ± 2.40.3±0.10.3 ± 0.1
Triacylglycerol三酰甘油酯PQQ+PQQ +1267±3401267 ± 340319±72319 ± 72298±97298 ± 97642±169642 ± 16916±816 ± 8623±163623 ± 16325±725 ± 7275±90275 ± 906±36 ± 3
PQQ-PQQ –254212392542 * ± 1239549**±240549 * * 240624299624 * ± 29913586991358 * ± 69936**±2136 * * 2113156721315 * ± 67245**±2245 * * 22586286586 * ± 2867.4±37.4 ± 3
PQQ+/-PQQ +/-2177†±7042177 ± 704533††±189533† + 189527†±172527 ± 1721112†±3401112 ± 34037††±2337 + + 231070†±3221070 ± 32247††±2547 + + 25483††±150483† + 1504±24 ± 2
Phospholipids (nmol fatty acid per g sample)2磷脂(每克样本中含有一毫克脂肪酸)2
LysoPC1PQQ+PQQ +543±58543 ± 58295±32295 ± 3237±5.837 ± 5.8208±29208 ± 294.8±1.34.8 ± 1.3204±29204 ± 298.3±1.18.3 ± 1.128±4.928 ± 4.91.5±0.91.5 ± 0.9
PQQ-PQQ –62168621 * ± 68323±43323 ± 4340±4.440 ± 4.4255**±21255 * * 216.4**±0.96.4 * * ± 0.9249**±20249 * * 209.5±1.59.5 ± 1.530±3.130 ± 3.11.9±2.01.9 ± 2.0
PQQ+/-PQQ +/-703††±6.8703† + 6.8360††±22360 + + 2245†±4.545 ± 4.5295††±19295 + + 198.7††±1.98.7 + + 1.9287††±17287 + + 1711††±1.511 + + 1.535±5.435 ± 5.41.4±0.51.4 ± 0.5
PC1PQQ+PQQ +2036±3292036 ± 329906±148906 ± 148107±15107 ± 151017±1671017 ± 16746±9.046 ± 9.0970±158970 ± 15831±6.031 ± 6.077±8.877 ± 8.84.7±1.14.7 ± 1.1
PQQ-PQQ –2254±6242254 ± 6241011±2211011 ± 221122±47122 ± 471101±3851101 ± 38555±2055 ± 201042±3731042 ± 37336±1636 ± 1691±2791 ± 277.0±3.77.0 ± 3.7
PQQ+/-PQQ +/-2462††±1062462 ± 1061103††±501103 + + 50121±4.5121 ± 4.51229††±521229 + + 5268†±4.068 ± 4.01161†±531161 ± 5336.7±4.236.7 ± 4.286±8.886 ± 8.86.3±1.56.3 ± 1.5
PEA1PQQ+PQQ +378±57378 ± 57166±25166 ± 2547±1747 ± 17152±34152 ± 345.6±1.45.6 ± 1.4146±33146 ± 334.2±1.44.2 ± 1.442±1642 ± 1611.2±3.011.2 ± 3.0
PQQ-PQQ –395±87395 ± 87165±40165 ± 4057±1057 ± 10162±41162 ± 417.3±1.57.3 ± 1.5154±40154 ± 404.8±1.04.8 ± 1.051±951 ± 910.4±1.610.4 ± 1.6
PQQ+/-PQQ +/-464†±15464 ± 15201†±15201 ± 1547±2147 ± 21203††±19203 + + 199.4††±2.49.4 ± 2.4194†±17194 ± 174.6±1.84.6 ± 1.841±1941 ± 1912.8±0.812.8 ± 0.8
Sphingomyelin鞘翅目PQQ+PQQ +195±84195 ± 84124±60124 ± 6045±1745 ± 1724±1124 ± 118±58 ± 517±717 ± 72±12 ± 142±1642 ± 160
PQQ-PQQ –165±84165 ± 84101±56101 ± 5642±2042 ± 2021±1021 ± 107±37 ± 315±615 ± 61.6±11.6 ± 140±1940 ± 190
PQQ+/-PQQ +/-263±135263 ± 135193±107193 ± 10742±1642 ± 1627±1327 ± 137±47 ± 418±718 ± 71±1.61 ± 1.643±1643 ± 160

Table 5 Pyrroloquinoline Quinone and Plasma Lipid37
1Values are mean ± SD; Abbreviations:FFA (free facty acid or non-esterified factty acids), LysoPC(lysophospholipid), PC(phosphocholine), PEA (N-acylphosphatidylethanolamine). 2For Comparisons: for PQQ+ vs. PQQ-, a single asterisk indicates p<0.05 and two asterisks indicate P<0.1 relative to the PQQ+group; for PQQ+ vs. PQQ +/-, a †indicates p<0.05 and †indicate P<0.1 relative to the PQQ+ group. Doi:10.1371/journal.pone.0021779.t002

表5吡咯并喹啉醌和血浆 lipid371值为 ± SD,简写为 FFA (游离脂肪酸或非酯化脂肪酸) ,LysoPC (溶血磷脂) ,PC (磷酸胆碱) ,PEA (n- 酰基磷脂酰乙醇胺)。2比较: PQQ + 与 PQQ-,一个星号表示 p < 0.05,两个星号表示 p < 0.1,PQQ + 与 PQQ +/-,a †表示 p < 0.05,+ + + + + +/-表示 p < 0.1。Doi: 10.1371/journal.pone. 0021779.T002

PQQ as vitamin

维生素 PQQ

PQQ has been addressed as vitamin in past,156 because was essential for normal growth, development157 and as a novice for B-vitamins.158 PQQ dietary status changed due to defects in lysine metabolism occur in PQQ-deprived rodents.159 Food products preserved by PQQ by inhibiting microorganism growth160 and can reduce all the problems like poor growth, lack of energy, poor learning, and failure to reproduce.161 PQQ is sold on a number of websites till date as vitamin like aliexpress, Swanson vitamins, amazon , molbase, life extensions, doctor murray even declared it as an essential nutrient, examine.com also state it having vitamin like mechanism in signaling and mitochondrial functions. It is also known as essential micronutrient by vegsource.com. natural health 365. Co declares it as a nutrient required for heart and brain health and in growth. The absorption of PQQ-Na2 decelerate strength by Vitamin C reaction and PQQH2, a reduced form of PQQ acting as anti-oxidant in all kind of life because of its foraging, scavenging and quenching of singlet oxygen activities (Figure 13).162

PQQ 在过去被称为维生素,因为它对正常生长发育至关重要,而且是维生素 b 的新手。158 PQQ 饮食状态的改变是由于缺乏 PQQ 鼠赖氨酸代谢缺陷引起的。PQQ 通过抑制微生物生长而保存的食品,可以减少生长不良、缺乏能量、学习能力差、不能繁殖等问题。161 PQQ 在许多网站上以维生素 aliexpress、 Swanson vitamins、 amazon、 molbase、寿命延长等形式出售,murray 医生甚至宣布它是一种必需营养素,exam.com 也声称它在信号传递和线粒体功能方面有类维生素机制。它也被 vegsource 网站称为必需微量营养素。自然健康365。公司声称它是心脏和大脑健康以及生长所需的营养物质。PQQ-Na2的吸收通过维生素 c 反应和 PQQH2降低强度,PQQH2是 PQQ 的一种还原形式,在各种生命中起抗氧化作用,因为它的觅食、清除和淬灭单线态氧活性(图13)Figure 13 图13Inter-conversion of PQQH2 to PQQ under the catalysis of Vit C; 在维生素 c 的催化下,PQQH2相互转化为 PQQ;42

PQQ role in plants

PQQ 在植物中的作用

PQQ in phosphate-solubilizing activities

PQQ 在解磷活性中的作用

The bacterial isolates synthesizing PQQ have higher tolerance to ultraviolet C radiation and high tolerance to DNA damage when grown in the absence of inorganic phosphate (PO43−).163 The Herbaspirillum seropedica (Gram negative) genome codes for GDH and Erwinia herbicolaencodes pqqE secreting minute molar PQQ levels to attain greater GDH activity for gluconic acid (33.46 mM) hyper-secretion.164 The extracellular space is acidified due to production of oxidized products and engrossed Ca 2+ in the phosphatic rocks release both H2PO4 and HPO42− in periplasmic space.165 PQQ acidifies extracellular medium by direct release of acid dissolving mineral phosphate to attain phosphate solubilization (Figure 16) and P. Putida strains with tn5 insertions (Table 6).166

合成 PQQ 的细菌菌株在无机磷酸盐(PO43 -)存在下生长,具有较强的抗紫外线 c 辐射能力和较强的 DNA 损伤能力。163革兰氏阴性草本植物基因组编码 GDH 和 Erwinia 除草剂基因组编码 pqqE 分泌微克分子 PQQ 水平,以获得更高的葡萄糖酸(33.46 mM)高分泌 GDH 活性。由于氧化产物的生成,细胞外液被酸化,磷质岩石中的钙全部被吸收,周质空间中的 H2PO4和 HPO42-都被释放出来。165 PQQ 通过直接释放酸溶性无机磷酸盐来酸化细胞外培养基(图16)和 Putida 菌株(图6)。166

Number数目Bacterial strains细菌菌株Property物业Plant weigh increase植物体重增加
1P.flourescens QAU67P.florescens QAU67Biocontrol, PGPR生物防治Elongation of lettuce roots, increased plant height in tomato plants生菜根伸长,番茄株高增加
2图2P.Ptutida QAU90P. ptutida QAU90Biocontrol, PGPR, inorganic phosphate solublization生物防治,PGPR,无机磷的溶解Increment in plant height and leaf surface area植株高度和叶表面积的增加
3图3P.flourescens QAU67-14P.florescens QAU67-14PGPR地质雷达24% difference in fresh weight of wild type than mutants野生型与突变型鲜重差异达24%
4图4P.Ptutida QAU90-4Ptutida QAU90-4PGPR地质雷达Increase in plant height and leaves area增加植株高度和叶面积
5P.Ptutida QAU90-23Ptutida QAU90-23PGPR ,capacity to solublize phosphate lower than QAU90PGPR 对磷酸盐的溶解能力低于 QAU90Slight increase of height in bean plants豆科植物株高略有增加
6图6Leclercia sp.QAU-66Phosphate solublization,PGPR解磷,PGPR10% increase in shoot and root length of phaseolusvulgaris,number of leaves also increased结果表明,随着紫花苜蓿地上部和根系长度的增加,叶片数量也增加

Table 6 Different strains having PGPR and phosphate solubilization activities12

表6具有 PGPR 和解磷活性的不同菌株12

PQQ impact on plant growth promotion

PQQ 对植物生长的促进作用

Figure 14 The microbial inoculation for biological growth with reduced biotechnological application could be a worthy practice to ease the nutrient accumulation phosphorus to plants.167 Naveed et al.2015 conducted a research to show the possible role of PQQ in plant growth promotion by PQQ/GDHmutagenesis renders functional inadequacies by conversion into gluconic acid, hence growth promotional activities(Figure 15).The plant growth promotion by rapid oxidation into gluconic acid of glucose acts as antioxidant to increase plant growth. The synthesis of gluconic acid from PQQ-dependent glucose oxidation is largely due to the presence of apo-GDH enhance phosphate solubilization.168 All of the pqq genes behave in a PqqH-dependent manner as their expression is only in nutrient-limiting conditions.169 Plant growth promotion by microbes such as AzospirillumRhizobiumare & Pseudomonas are based on improved nutrient accretion and hormonal stimulation. In agricultural biotechnology the beneficial plant–microbe interactions, and microbial inoculants used as biofertilizers, biopesticides, plant strengtheners, and phytostimulators. These genomic technologies for conventional and organic agriculture worldwide are environmentally friendly strategies.170 Plant growth can be affected by a number of biochemical changes like phosphate solubilization, production of siderophore, rhizosphere engineering, N2-fixation, production of Phytohormones, antifungal-activity, generation of VOCs, initiation of ISR, enhancing symbiosis, intervention with toxin-production for pathogens.171 PQQ dependent GDH being responsible for mineral phosphate solubilization showing a decrease in IAA canalization. By adding cluster of pqq gene and not only pqqE is highly required in H. Seropedicae for phosphate solubilization.172 PQQ promotes plant growth in vivo but the mechanisms are ambiguous and it would be very beneficial in near future to envisage a large number PGPR for PQQ-genesis.173 Plant growth promoting rhizobacteria of Pseudomonas and Bacillus spp exert a great pressure by Phytohormones, inorganic phosphate solubilization, enhanced iron nutrition and volatile-compounds affecting signaling pathways in plants174 PQQ can act as biofertilizer in agricultural crops by genetic manipulation of R. Leguminosarum with enhanced mineral phosphate solubilization.175‒177 PGPR are known to improve plant performance in many different ways, operating via a multitude of molecular, physiological, and biochemical pathways.178 PQQ attributes to plant growth solubilization by glucose acting as carbon source for GDH substrate and its role in plant growth promotion are regulated by pqqC locus due to its antioxidant properties. PQQ can act as an antioxidant or a pro-oxidant in different biological systems and in bacteria may be consequent to scavenging of free radical scavenging mechanism.179

167 Naveed et al. 2015年进行了一项研究,以显示 PQQ 通过 PQQ/gdhentation 转化为葡萄糖酸从而使功能缺陷得以改善,从而促进植物生长(图15)。葡萄糖快速氧化成葡萄糖酸促进植物生长,是促进植物生长的抗氧化剂。Pqq 依赖的葡萄糖氧化合成葡萄糖酸主要是由于载脂蛋白-葡萄糖脱氢酶的存在增强了溶磷作用。在农业生物技术中,有益的植物-微生物相互作用,微生物接种剂用作生物肥料、生物农药、植物强化剂和植物刺激剂。170植物的生长可能受到一系列生化变化的影响,例如磷酸盐溶解、铁载体的产生、根际工程、固氮、 Phytohormones 的产生、抗真菌挥发性有机化合物的产生、 ISR 的启动、增强共生、干预病原体的毒素产生。171 PQQ 依赖的 GDH 负责矿物质溶解磷酸盐,这表明 IAA 的开放性下降。通过添加 pqq 基因簇,不仅 pqqE 对嗜血支原体增溶磷酸盐有很高的要求。172 PQQ 对植物体内生长有促进作用,但其作用机制尚不明确,有望在不久的将来获得大量 PGPR 用于 PQQ-genesis。173假单胞菌和芽孢杆菌的促生根细菌通过植物激素、无机磷溶解、铁营养增强和挥发性化合物对信号通路产生巨大压力,PQQ 基因通过对豆科牧草的遗传操纵和矿物磷溶解作用的增强,在农作物中起到生物肥料的作用。175-177 PGPR 是众所周知的,通过许多分子、生理和生化途径,以许多不同的方式改善植物的性能。178 PQQ 基因在葡萄糖作为碳源促进植物生长的过程中,由于其抗氧化特性,其在促进植物生长中的作用受到 pqqC 位点的调控。PQQ 在不同的生物系统和细菌中可以作为抗氧化剂或氧化促进剂,这可能是由于 PQQ 清除自由基的机制Figure 14 图14Log Cfu increase in per-gram of root 每克根中菌落计数增加19Figure 15 图15Growth promotion appositional activities of Phaseolus vulgaris by P. Putida with GDH mutant. 利用葡聚糖脱氢酶突变体促进菜豆的生长附加活性19Figure 16 图16Diagrammatic presentation of ISR characteristics and mechanism. ISR 特征和机制的图示表示

PQQ in antifungal activities

PQQ 在抗真菌活性中的作用

The protection from phytophathogens is provided by different mechanisms like antibiotics synthesis, secretion of siderophores, assembly and production of enzymes inhibiting the phytophathogens and stimulation of the systemic resistance of the plants180 Rahnella aquatilis can producing an anti-bacterial medium that hinders the proliferation of A. Vitis playing a role in biocontrol of A. Vitis.181The pqqC gene have been recognized to have antifungal activites, because they encodes pqq synthesis protein C182 the molecular mechanisms for P. Kilonensis well characterized for the advancement of fungicides and unparallel antibiotics.183 The synthesis of metabolites (secondary) in Pseudomonas species and exo-enzymes being modulated via GacS-GacA, Gac-system, mutations in gacS causes increased generation of 2-ketogluconic acid and gluconic acid, suppressing fungal growth, bacterial and fungal oomycete pathogens.184 GDH dependent PQQ acidifies periplasmic space by oxidation, playing bioenergetics role, scavenging free radicals and foraging superoxides might be involved in antifungal activities by altering intracellular.

通过抗生素合成、铁载体分泌、抑制植物病原菌的酶的组装和产生以及刺激180种植物的系统抗性等多种机制提供植物病原菌的保护作用,可以产生一种抑制葡萄白粉病菌增殖的抗菌培养基,在葡萄白粉病的生物防治中发挥作用。181 pqqC 基因编码 pqq 合成蛋白 C182,具有抗真菌活性,是杀菌剂和抗生素发展的重要分子机制。183假单胞菌代谢产物(次级代谢产物)的合成和外源酶的调控通过 GacS-GacA,gac-系统,gacS 突变导致2- 酮葡萄糖酸和葡萄糖酸的产生增加,抑制真菌生长,抑制细菌和真菌病原菌。184 GDH 依赖的 PQQ 通过氧化作用酸化周质空间,发挥生物能量学作用,清除自由基和觅食超氧化物可能通过改变细胞内活性参与抗真菌活性。

Induced systematic resistance in plants

植物诱导的系统抗性

Rhizobacteria usually cause induced systemic resistance (ISR), which is considered an improved defensive ability.185 The pqqA and B genes are involved in assembly and manufacturing of 2-ketogluconic acid from glucose, induction of systemic resistance, by affecting metabolic pathways (Figure 16).186 SAR is activated by a pathogen attack and is noticed by the regular enhancement of salicylic-acid by PR,187 ISR monitored by various signaling pathways and genetic expression triggered by PGPR.188 PGPR include aspects of plant growth promotion and induced systematic resistance in crop production.. Signal transduction pathways of Pseudomonas PGPR in plants Arabidopsis and rice induces ISR, liberated of Jasmonic Acid, SA and Npr1 were involved in the ISR trigger by VOCs of Bacillus amyloliquefaciens .Fluorescent Pseudomonas spp. have been reported for plant growth-promoting effects by silencing or putting down plant pathogenesis. The inoculation of virulent strain Cm988 on seedlings, caused no vital resistance for C. Miyabeanus, JA higher concentrations might not initiate defenses against C. Miyabeanus. Excessive colonization is not required for ISR in the roots for exertion of many biocontrol mechanisms and pathogen related disease (Figure 17). PQQ genes are sensitive to bacterial response for oxidative-stress in induced systematic resistance. Their identification based on molecular analysis such as 16S rRNA gene sequence analysis provides us an insight into microbial diversity which is a valuable future resource in various industrial and biotechnological processes.

185 pqqA 和 b 基因参与了葡萄糖中2- 酮葡萄糖酸的组装和生产,通过影响代谢途径诱导系统抗性(图16)。186 SAR 被病原体攻击激活,通过 PR 定期增强水杨酸、187 ISR 被各种信号途径监测和 PGPR 触发的遗传表达而被注意到。188 PGPR 包括促进植物生长和在作物生产中诱导系统抗性的方面。.拟南芥和水稻中假单胞菌 PGPR 的信号转导通路诱导 ISR,释放出茉莉酸、 SA 和 Npr1参与了解淀粉芽孢杆菌挥发性有机化合物触发 ISR。荧光假单胞菌通过沉默或降低植物病理机制对植物生长的促进作用已被报道。用强毒株 Cm988接种宫崎菌苗木,对宫崎菌没有致命抗性,但较高浓度的宫崎菌不能引起对宫崎菌的抗性。许多生物防治机制和病原相关疾病的发挥不需要 ISR 在根部过度定植(图17)。PQQ 基因对细菌诱导的系统抗性中的氧化应激反应敏感。他们的鉴定基于分子分析,如16S rRNA 基因序列分析,为我们提供了一个洞察微生物多样性,这是一个宝贵的未来资源,在各种工业和生物技术过程。Figure 17 图17(A) ISR in Pseudomonas spp.(Loon 2007) (B) Induced systemic resistance against soft rot pathogen Erwinia carotovora in tobacco seedlings. (a)假单胞菌 ISR (Loon 2007)(b)诱导烟草幼苗对软腐病菌胡萝卜软腐病菌的系统抗性59

PQQ and modern technologies

PQQ 与现代科技

PQQ in Bio-electro catalysis

PQQ 在生物电催化中的应用

PQQ-GDH is a redox coenzyme on Au-ITO electrodes, used for the production of bioelectronics-units allowing electrochemical transduction for enzyme accumulation alteration by 1- fold bioelectrocatalytic activity (Figure 18). These biosensors are expected to play a crucial role in the advancement of life expectancy and construction of biosensors for industrial. The oxygen-independent, (PQQ–GDH) can be used to construct an glucose oxidase based electrode by using polyethylene glycol-diglycidyl ether (PEGDGE) obvious cross-linker purposes unfavorable attachment to a non electro active subunit. PQQ functional Au-NPs electrodes with 1.4nm DNA detection and telomerase activity by chemiluminescence as outer signals. PQQ-GDH in direct bioelectrocatalytic enzyme electrodes based on sulfonated polyanilines by localization of proteins in multi layers on electrodes, devising fast electron transfer phenomenon executable incyt c-DNA4 and PQQ dependent GDH electrodes. The GDH and PQQ based bioelectrocatalytic electrodes used for immobilization of bulk of enzyme and catalytic current can be used for production of more capable bioelectronics units.

PQQ-GDH 是 Au-ITO 电极上的一种氧化还原辅酶,用于生产生物电子学单元,通过1倍的生物电催化活性允许电化学转导进行酶积累改变(图18)。这些生物传感器有望在提高预期寿命和工业用生物传感器的构建方面发挥关键作用。利用聚乙二醇二缩水甘油醚(PEGDGE)明显的交联作用,不利于与非电活性亚基的结合,可以利用 PQQ-GDH 构建葡萄糖氧化酶基电极。PQQ 功能 Au-NPs 电极1.4 nm DNA 检测及端粒酶活性化学发光作为外信号。基于磺化聚苯胺的直接生物电催化酶电极,通过在电极上定位多层蛋白质,设计快速电子转移现象可执行的 ccyt c-DNA4和 PQQ 依赖的 GDH 电极。以 GDH 和 PQQ 为基础的生物电催化电极用于固定大量的酶和催化电流,可用于生产功能更强的生物电子器件。Figure 18 图18Schematic diagram of layered composition and operation of the modified electrode. 修饰电极的分层组成和操作示意图27

PQQ in polymer technology

聚合物技术中的 PQQ

The apo-GDH/PQQ when loaded into poly methyl methacrylate nanospheres for highest application in polymer bioaffinity-assays shows detection capability.100 Both the Gram-negative Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Acinetobacter calcoaceticus, Shewanella oneidens is and the other Gram-positive Bacillus subtilis bacteria can be immobilized onto the conducting polymers by deposition of electrochemical process.78 Polymer forms in Sulfonated polyanilines for investigating structural composition and properties for direct electron transfer with PQQ-GD.72 The latest technologies should be developed based on PQQ-GDH for conductive polymeric fibers and nanospheres.189

载载 apo-GDH/PQQ 的聚甲基丙烯酸甲酯纳米球用于聚合物生物亲和性测定时,表现出了良好的检测能力。聚苯胺磺化聚合物的结构组成和性能的研究应以聚合物纤维和纳米球的 PQQ-GDH 为基础开发最新的技术。189

PQQ as nanoparticles

作为纳米粒子的 PQQ

PQQ-GDHfunctionalized Au nanoparticles (Au-NPs) act as a charge-transfer mediator.87,88Nanomaterials are used as a conductive bridge for oxidation/reduction as enzymatic biocatalyst with heme-c containing PQQ90 S-PQQ/GDH from Acinetobacter calcoaceticuswhen covalently attached to electro-polymerized polyaniline co-polymer film on MWCNT mediated gold electrode showed efficient bio-electro catalytic conversion of glucose for biofuel cell (Figure 19).Involving both the direct and mediated electron transfer (DET and MET) the mechanisms for which involve (MWCNTs) with different immobilization techniques.87 The nanoparticles based therapies for curing deadly disorders can be brought to commercial application the evidence being its involvement in DJ-1, JNK and caspase pathway activation.

87,88纳米材料作为酶促生物催化剂,将含有 PQQ90 S-PQQ/GDH 的血红素 c 与电聚合聚苯胺共聚物膜共价连接到 MWCNT 金电极上,表现出生物电催化葡萄糖转化细胞的效果(图19)。基于纳米粒子的治疗致命疾病的方法可以商业化应用,证据是它参与了 DJ-1、 JNK 和 caspase 通路的激活。Figure 19 图19Au-MWNT electrode in 1mM PQQ solution involved for conversion of Glucose to Glucono-lactone. 1mM PQQ 溶液中金-多壁碳纳米管电极参与葡萄糖转化为葡萄糖内酯36

Bioinformatics based structural analysis

基于生物信息学的结构分析

PQQ-GDH X-ray structure prediction shows a propeller, fold super barrel made up of 8-sheet `propeller blades’ having tryptophan docking motifs. It have three domains having heme b at N-terminal and a cytochrome-domain with catalytic center comprising of PQQ as a co-factor. Their identification based on molecular analysis such as 16S rRNA gene sequence analysis provides us an insight into microbial diversity which is a valuable future resource in various industrial and biotechnological processes.

Gdh x 射线结构预测显示,一个螺旋桨,折叠超级桶组成的8片’螺旋桨叶片’有色氨酸对接图案。它的 n 端有三个亚铁血红素 b 结构域和一个以 PQQ 为辅助因子的催化中心的细胞色素结构域。他们的鉴定基于分子分析,如16S rRNA 基因序列分析,为我们提供了一个洞察微生物多样性,这是一个宝贵的未来资源,在各种工业和生物技术过程。

The mGDH with PQQ-dependent quinoproteins plays a pivotal role in evolutionary process by advances in molecular structure.18 PQQ has a coplanar tryptophan and a disulphide ring as its active site residual location, hence structure is derived from adjacent cysteine residues requiring Ca2+ for activity and uses cytochrome cL as its electron acceptor.80‒84m-GDH in Escherichia coli have molecular structure and catalytic reaction site, N-terminal domain to anchor the domain in periplasmic t and activity shown by X-ray modeled structure of the α-subunit in PQQ active site(Figure 20).161‒165 The m-GDH of E.Coli is a securely fixed with ubiquinone localized coenzyeme (PQQ).120 The structural designation of PQQ-GDH protein could be elucidated by Pfam, I-TASSER and Inter Pro Scan.110 The amino acid sequence shows low homology with PQQ-GDH, BLAST analysis revealed the occurrence of numerous genes coding homologous proteins of fungi, bacteria, amoebozoa, archea and bacteria.168The hydrophobic interactions play a role in PQQ structure by Arg side-chain and calcium ions being ligated to the ortho group in active site, with their proposed catalytic activity to polarize C5-O5 bond of PQQ. The pqqB for the biosynthesis of and pqqC claims an acceptor (Table 7).141 Five transmembrane segments has been determined in N-terminal region which anchors the membrane-protein, while the C-terminal region having a huge conserved PQQ active residues embedded for its catalytic purpose in binding site. Other than PqqA, PqqE the PqqD which is a 10-kDa protein it is essential for PQQ production. PqqD. The GDH of Leclercia sp. QAU-66 contain 377 amino acid putative protein have c and n-terminal domain with a trans-membrane helical coils secured in cell membrane of protein. A correspondent also pondered by that GDH anchorsin trans-membrane due to five genes with hydrophobic domain at n-terminal catalytic endeavor at c-terminal of conserved PQQ genes.

随着分子结构的进步,含有 pqq 依赖的藜麦蛋白的 mGDH 在进化过程中起着关键作用。18 PQQ 有一个共面色氨酸和一个二硫化物环作为其活性位点的残留位置,因此其结构来源于相邻的半胱氨酸残基,其活性需要 Ca2 + ,并以细胞色素 c l 作为其电子受体。大肠桿菌的80-84m-GDH 具有分子结构和催化反应位点,n 端结构域锚定周质中的结构域,PQQ 活性位点的 x 射线模拟结构显示其活性(图20)。161-165大肠杆菌 m-GDH 是一种与泛醌定位辅酶基因(PQQ)安全固定的基因。120 PQQ-GDH 蛋白的结构设计可用 Pfam、 I-TASSER 和 Inter Pro Scan 进行鉴定。110氨基酸序列与 PQQ-GDH 基因同源性较低,BLAST 分析表明,编码真菌、细菌、变形虫、太古虫和细菌等同源蛋白的基因较多。168在 PQQ 结构中,疏水相互作用通过 Arg 侧链和活性中心的邻位基团连接钙离子对 PQQ 结构起作用,并提出了它们极化 PQQ C5-O5键的催化活性。141在 n 端已经确定了5个跨膜片段,它们锚定了膜蛋白,而 c 端有一个巨大的保守的 PQQ 活性残基嵌入其结合位点。除了 PqqA,PqqE 的 pqd 是一个10-kDa 的蛋白质,它是必不可少的 PQQ 生产。PqqD.英国莱克勒语言学会。QAU-66含有377个推测的氨基酸蛋白,其 c 端和 n 端都有一个跨膜螺旋线圈固定在蛋白质细胞膜上。另外,在保守的 PQQ 基因的 c 端有5个具有疏水结构域的基因导致 GDH 基因跨膜。Table 7 表7Properties and structure of PQQ operon PQQ 操纵子的性质和结构

S.NO没有PQQ affecting major pathways影响主要通路的 PQQ
1STAT signal transducer and activator of transcriptionSTAT 信号转导子与转录激活子Tumorigenesis in epigenetic and signal pathways表观遗传和信号通路中的肿瘤发生12图12
2图2MAPKmitogen-activated protein kinase丝裂原活化蛋白激酶BAX translocation to mitochondria, CREB activation, accumulation of ROS, decrease in ATP levels, MMP, down-regulation of Bcl-2 proteinBAX 向线粒体移位,CREB 激活,ROS 积累,ATP 水平下降,MMP,Bcl-2蛋白下调19图19
3图3JAK(Janus Kinase)杰纳斯激酶(Janus Kinase)Cell proliferation, differentiation, survival, and apoptosis.细胞增殖、分化、存活和凋亡。9图9
4图4PGC-1αPgc-1Mitochondrial biogenesis.线粒体生物发生。8图8
5JNK signaling pathwayJNK 信号通路Protects damage by suppressing intracellular ROS and apoptosis通过抑制细胞内 ROS 和细胞凋亡来保护损伤7图7
6图6RANKLFormation of osteoclasts, decrease of F4/80 macrophage maturation破骨细胞形成、 F4/80巨噬细胞成熟度下降9图9
7图7Entner-Doudoroff pathwayEntner-Doudoroff 通道Induced for oxidative glucose metabolism by PQQ-GDHPQQ-GDH 诱导葡萄糖氧化代谢的研究10图10
8图8Metabolic pathways代谢途径Mitochondrial dysfunction and cell death线粒体功能障碍与细胞死亡12图12
9图9PI3K/Akt signal pathwayPI3K/Akt 信号通路Up regulation , stimulation, production and release of NGF神经生长因子的上调、刺激、产生和释放26图26
10图10ERK1/2 pathwayERK1/2通路Activation, inhibition of intracellular ROS production, modulation of Bcl-2 and Bax, downregulation of p27 production and cell cycle regulation活化、抑制细胞内活性氧产生、调节 Bcl-2和 Bax、下调 p27产生和细胞周期调控23, 4523,45
11图11mTORRadiation protection in cancer treatment癌症治疗中的辐射防护57
12图12EGFR signalingEGFR 信号Intracellular ROS production, tyrosine de phosphorylation胞内活性氧产生,酪氨酸脱磷酸化40
13图13Hexose monophosphate pathway单磷酸己糖途径Phosphorylate gluconic acid formation磷酸化葡萄糖酸的形成39图39
14图14Pentose phosphate pathway磷酸戊糖途径Complete glycolytic functions完整的糖酵解功能67
15图152,5-Diketogluconic Acid Pathway2,5-二酮葡萄糖酸途径Oxidation of glucose phosphorylation of ADP, metabolized by Entner-Doudoroff pathway糖代谢途径 Entner-Doudoroff 氧化 ADP 的葡萄糖磷酸化67
16图162,5-dkg Pathway2,5-dkg 通路The gdh genes with high homology at C-terminal ends .The gene products of yqfE and yafB catalyzes the reduction of 2,5- DKG to 2-KLG.在 c 末端具有高同源性的 gdh 基因。yqfE 和 yafB 的基因产物催化2,5-DKG 还原为2-KLG。22图22
17图17PQQ biosynthetic pathwayPQQ 生物合成途径PQQ being synthesized from peptide containing tyrosine and glutamic acid; Fe, Zn2+, Ca2+ metal ions, Tyr and Glu residuesPQQ 是由含有酪氨酸和谷氨酸的多肽、铁、锌离子、钙离子、酪氨酸和谷氨酸残基合成的13,14
18图18Ras signaling pathwayRas 信号通路Cell protection against NO induced inhibition of cell proliferation, promoting DNA synthesis一氧化氮诱导的细胞增殖抑制,促进 DNA 合成12图12

Table 8 PQQ affecting diverse signaling pathways

表8 PQQ 影响多种信号通路

Role of PQQ in different metabolismsPQQ 在不同代谢中的作用
Type of metabolism新陈代谢的类型Role角色References参考资料
1Lysine metabolism赖氨酸代谢Alpha-aminoadipic acid (alphaAA), made from lysine in mitochondria , enters into biotin metabolism氨基己二酸(alphaa)由线粒体中的赖氨酸合成,进入生物素代谢22图22
2图2Selenium metabolism硒代谢TrxR119图19
3图3Mitochondrial-related metabolism线粒体相关代谢Plasma C-reactive protein, interleukin (IL)-6 levels血浆 C反应蛋白、白细胞介素 -6水平34图34
4图4Lipid Metabolism脂质代谢High and low density lipoprotein, elevated levels of (TG).高、低密度脂蛋白、 TG 水平升高。23‒2823-28
5Energy metabolism能量代谢Improved energy and lipid relationship in mitochondrial amount线粒体数量与能量和脂质关系的改善57
6图6Glucose metabolism葡萄糖代谢Oxidation of glucose to gluconate in the periplasm.葡萄糖在胞质中氧化成葡萄糖酸盐。67
7图7Sugar metabolism糖代谢Conversion of glucose into gluconic acid葡萄糖转化为葡萄糖酸的过程96
8图8Metabolism of aromatic compounds芳香族化合物的代谢Quinate/shikimate dehydrogenase of Acinetobacter sp不动杆菌奎尼特/莽草酸脱氢酶的研究100
9图9TCA cycle metabolitesTCA 循环代谢物Changes in C-reactive protein and Il-6 levelsC反应蛋白和 Il-6水平的变化65
10图10Intracellular metabolism细胞内新陈代谢Regulatory and bioenergetics role调节和生物能学作用68
11图11Carbohydrate Metabolism糖代谢Oxidative formation of acetic acid, D-gluconate, 2- or 5-keto-D-gluconate, Lsorbose, and dihydroxyacetone.乙酸、 d- 葡萄糖酸盐、2-或5- 酮-d- 葡萄糖酸盐、 Lsorbose 和二羟丙酮的氧化形成。92
12图12Vitamin metabolism维生素新陈代谢Activation of SLC25A 16 geneSlc25a16基因的激活(http://biograph.be/concept/graph/C1157231/IPR011842)( http://biograph.be/concept/graph/c1157231/ipr011842)

Table 9 Role of PQQ in different metabolisms

表9 PQQ 在不同代谢中的作用Figure 20 图20(a) PSIPRED representation of QAU-66 (secondary structure) and GDH and Phosphorylation (b) Functional domains of QAU-66 GDH (A&B) predicted by INTERPROSCAN and COFACTOR respectively (c) Predicted 3D model of Leclercia sp. QAU-66 GDH obtained from I-TASSER and visualized on Jmol. (a)分别用 INTERPROSCAN 和 COFACTOR 预测 QAU-66(二级结构)和 GDH 的 PSIPRED 表示,以及磷酸化(Phosphorylation)(b) QAU-66 GDH (a & b)的功能域(c)预测 Leclercia sp。从 I-TASSER 提取 qau-66gdh,并在 Jmol 上进行可视化19

Conclusion

总结

The exceptional properties of PQQ has diverse application in agriculture by providing tolerance to DNA impairment, PGPR, as biofertilizer by hormonal stimulation and IAA production, Gac-system in antifungal activities, increment in plant growth by symbiosis and enhanced ISR by activation of pathogen related protein and salicyclic acid(SA) accumulation. PQQ on C-terminal has conserved nature, mGDH has binding activity by bivalent metal ions and S-GDH-PQQ is reduced to PQQH2 and oxidized to PQQ by hydride ion transfer. Out of six persons PqqC was found to be more important in sequential steps of PQQ biosynthesis. It generates energy for nuclear, cellular and mitochondrial energy. NAD+ uses molecular oxygen for conversion to reduced NADH (PQQH2).The PQQ-GDH protein docking; binding motifs and cofactor analysis by bioinformatics tools are quite useful in industrial, medical, agricultural and therapeutic applications. The post translational modifications of PQQ active site alters the catalytic activity consequently causing phosphate solubilization and gluconic acid conversion.PQQ is prevalent as electrochemical transduction enzyme, bioelectrocatalytic and biosensor for construction of PQQ-GDH electrodes for commercial production of sulfonated polyanilines, polymer films, nanospheres, nanoparticles, MWCNT and biofuel cells.

PQQ 具有抗 DNA 损伤的特性,PGPR 作为激素刺激和 IAA 生产的生物肥料,gac 系统的抗真菌活性,水杨酸共生促进植物生长,通过激活病原菌相关蛋白和环状酸(SA)积累增强 ISR,在农业上有着广泛的应用。PQQ 在 c 端具有保守性,mGDH 具有二价金属离子的结合活性,s-gdh-PQQ 被还原成 pqh2,通过氢化物离子转移氧化成 PQQ。其中 PqqC 在 PQQ 生物合成的连续步骤中起着重要作用。它为核能、细胞能和线粒体能产生能量。NAD + 利用分子氧转化为还原型 NADH (PQQH2)。利用生物信息学工具进行 PQQ-GDH 蛋白对接、结合序列分析和辅因子分析在工业、医学、农业和医疗应用中都非常有用。PQQ 作为电化学转导酶、生物电催化和生物传感器广泛应用于磺化聚苯胺、聚合物薄膜、纳米球、纳米颗粒、 MWCNT 和生物燃料电池的制备。

It has bioenergetics applications as biocatalyst providing force for electron transfer, cellular growth stimulant, biocontrol, antibiotic resistance, energy transduction, ATP synthesis, and intracellular signaling. PQQ plays a fundamental role in human health by acting as NGF enhancer via activation of ERK1/2 pathway (Anti-neurodegenerative), inhibitor of TRP-1(Anti-melanogenic),T-cell proliferation and Interleukin-2 reduction (Immunogenic agent), PGC-1alpha pathway activation(sleep and relaxant agent), Free radical scavenger phosphorylates MAPK protein(Anti-cancer) , glutathione reduction(Anti-fibrogenic), activator of cAMP and CREB, reduction of MDA(cardioprotective), protein tyrosine phosphatase(insulin resistance), a controverter vitamin and enhancer of Sirt1 and Sirt3.

它具有生物能量学的应用,作为生物催化剂提供力量的电子转移,细胞生长刺激剂,生物控制,抗生素抗药性,能量转导,ATP 合成,和细胞内信号。PQQ 通过激活 ERK1/2通路(抗神经退行性)、 TRP-1抑制剂(抗黑素生成性)、 t 细胞增殖和白细胞介素2降低(免疫原性剂)、 pgc-1α 通路激活(睡眠和松弛剂)、自由基清除剂磷酸化 MAPK 蛋白(抗癌)、谷胱甘肽还原(抗原性)、 cAMP 和 CREB、 MDA 减少(心肌保护性)、蛋白酪氨酸磷酸酶蛋白(胰岛素抵抗性)、 Sirt1和 Sirt3的调节和增强剂等途径,在人类健康中发挥着重要作用。

PQQ has been assigned many important functions as antioxidant and its role to scavenge free radicals to save cells from oxidative damage in animals. PQQ has many pharmacological applications in future. Since, researchers have discovered many important roles of PQQ on the cellular processes, however the consideration is not yet complete. It has obvious roles in metabolic, epigenetic and cellular pathways. PQQ has even been discovered as an extremely important substance on earth which can have a possible role in evolution of life on earth. So, there is a need to understand mechanism of action behind all these spectacular properties of PQQ.

PQQ 作为一种抗氧化剂,具有清除自由基、保护细胞免受氧化损伤的作用。PQQ 具有广阔的药理应用前景。自年以来,研究人员发现了 PQQ 在细胞过程中的许多重要作用,但这方面的研究尚未完成。它在代谢、表观遗传和细胞通路中有明显的作用。PQQ 甚至被发现为地球上一种极其重要的物质,它可能在地球生命的进化中发挥作用。因此,有必要了解 PQQ 所有这些壮观特性背后的作用机制。

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