Pyrroloquinoline Quinone(PQQ研究报告)


Pyrroloquinoline Quinone

Karen R. Jonscher, Robert B. Rucker, in Dietary Interventions in Liver Disease, 2019

1 Introduction: Pyrroloquinoline Quinone

Pyrroloquinoline quinone (PQQ) is a compound found ubiquitously in plants, many simple and single cell eukaryotes (e.g., yeast), and certain bacteria. Early studies in mice and rats revealed that diets deficient in PQQ resulted in growth impairment, compromised immune response, abnormal reproductive performance, and metabolic inflexibility.1–6 The first suggestions that PQQ is biologically relevant evolved from observations that some bacterial dehydrogenases utilized cofactors other than those derived from pyridine or flavin derivatives as redox catalysts.7 Hauge8 was the first to report that the glucose dehydrogenase in Bacterium anitratumcontained a novel redox prosthetic group. Subsequent work (cf. studies by Anthony, Frank, Duine, Ameyama, Adachi, and coworkers7,9,10) confirmed Hauge’s observations and suggested the cofactor was a quinone. In 1979, Salisbury et al.11 reported the quinone structure to be PQQ (Fig. 13.1). It was soon recognized that in addition to glucose dehydrogenases, PQQ serves as a cofactor for multiple types of bacterial alcohol dehydrogenases.12–14

吡咯并喹啉醌(PQQ)是一种普遍存在于植物、许多单细胞真核生物(如酵母)和某些细菌中的化合物。在小鼠和大鼠中的早期研究表明,缺乏 PQQ 的饮食会导致生长障碍、免疫反应受损、生殖能力异常和代谢缺陷。1-6通过观察一些细菌的脱氢酶利用除吡啶或黄素衍生物之外的辅助因子作为氧化还原催化剂,首次提出 PQQ 在生物学上是相关的。随后的工作(参考 Anthony,Frank,Duine,Ameyama,Adachi 和同事的研究7,9,10)证实了 Hauge 的观察结果,并表明辅因子是醌。1979年,Salisbury 等人报道醌结构为 PQQ (图13.1)。人们很快认识到,除了葡萄糖脱氢酶外,PQQ 还是多种类型的细菌乙醇脱氢酶的辅助因子

The principal source of PQQ for animals is the diet. There is no evidence that PQQ is made in animal tissues and organs. For example, intestinal bacteria such as Escherichia coli do not synthesize PQQ.15 In plants, PQQ comes directly from soil and soil bacteria. The major bacterial sources of PQQ are methylotrophic,16 rhizobium (common soil bacteria),17 and acetobacter bacteria.18,19 It is also important to note that the PQQ-like compounds in soil initially came from and are found in interstellar dust.20 Accordingly, it may be inferred that plants and animals have been exposed to PQQ throughout evolutionary biology on earth.

对动物来说,PQQ 的主要来源是饮食。没有证据表明 PQQ 是在动物组织和器官中制造的。例如,像大肠桿菌这样的肠道细菌不会合成 PQQ。在植物中,PQQ 直接来自土壤和土壤细菌。PQQ 的主要细菌来源是甲醇营养菌、16种根瘤菌(常见的土壤细菌)、17种醋酸杆菌。18、19还必须注意的是,土壤中的类 PQQ 化合物最初来自星际尘埃,并在其中发现。

In animals, PQQ participates in a range of biological functions with apparent survival benefits (e.g., optimization of neonatal growth, reproductive performance, hepatic and muscular functions, and mitochondriogenesis), as well as benefits to neuroprotection and improved cognitive, immune, and antioxidant functions.14,21,22Although PQQ is not currently viewed as a “vitamin,” it does serve as a critical accessory factor important in modulating the activity of NAD-requiring dehydrogenases. Moreover, of the known biofactors in foods, PQQ is the only biofactor for which the effects of a dietary deficiency have been demonstrated.14,21,22 PQQ is also ubiquitously present in all plant and animal tissues analyzed to date,23–28 which is not the case for many of the other biofactors derived from foods (e.g., resveratrol, quercetin or compounds in the anthocyanin family).29

在动物中,PQQ 参与一系列生物功能,具有明显的生存益处(例如,优化新生儿生长、繁殖性能、肝脏和肌肉功能以及线粒体发生) ,并有利于神经保护和改善认知、免疫和抗氧化功能。14,21,22虽然 PQQ 目前不被视为一种“维生素” ,但它确实是调节 nad- 需求脱氢酶活性的一个重要的辅助因子。此外,在已知的食物中的生物因子中,PQQ 是唯一被证明有饮食缺乏影响的生物因子。14,21,22 PQQ 也广泛存在于所有动植物组织中,23-28不是从食物中提取的许多其他生物因子(如白藜芦醇、槲皮素或花青素家族中的化合物)

Measured concentrations of PQQ in various plant and animal tissues are given in Table 13.1. The amounts reflect “free” or extractable PQQ. However, PQQ also readily forms adducts with nucleophilic reagents such as methanol, aldehydes, ketones, urea, ammonia, and amines.30 Although not well characterized, many of the reactions related to adduct formation appear to be reversible. Notably, a significant amino acid–derived condensation product is imidazolopyrroloquinoline (IPQ) or imidazolopyrroloquinoline with an attached amino acid side chain or R-group31 (Fig. 13.1). IPQ has been shown in vivo to have antioxidant, radical scavenging capability like that of PQQ.32 Therefore, measurements of “free” PQQ do not reflect total tissue pools that include adducted species, some of which, like IPQ, may be bioactive and important to quantify. Quantitative methods to directly measure the total tissue pools of PQQ, including PQQ protein and amino acid adducts, have yet to be fully developed and standardized.

在各种植物和动物组织中测量的 PQQ 浓度见表13.1。数额反映了“免费”或可提取的 PQQ。然而,PQQ 也很容易与亲核试剂如甲醇、醛、酮、尿素、氨和胺形成加合物。值得注意的是,一个重要的氨基酸衍生的缩合产物是咪唑并吡咯喹啉(IPQ)或咪唑并吡咯喹啉与附着的氨基酸侧链或 r 组31(图13.1)。因此,测量“游离” PQQ 并不能反映包括内生物种在内的整个组织库,其中一些组织库,如 IPQ,可能具有生物活性,需要进行定量。直接测定 PQQ 组织总库的定量方法,包括 PQQ 蛋白和氨基酸加合物,尚未得到充分发展和规范。

Table 13.1. Pyrroloquinoline Quinone (PQQ) Content of Selected Foods, Tissues, and Fluidsa

表13.1. 精选食品、组织和吡咯并喹啉醌的含量

PQQ Source PQQ 资源μg/100 G/100 g Fresh Weight or 100 mL Volumeμg/1000 G/1000 Kilocalories or 4184 KilojoulesReferences (Detection Method) 参考资料(检测方法)b
Vegetables 蔬菜
Parsley 欧芹3.490–100 90-10026 (GC, MS) (GC,MS)
Potatoes 土豆1.7∼22 原文地址: ∼2226 (GC, MS) (GC,MS)
Sweet potatoes 红薯1.3∼15 1526 (GC, MS) (GC,MS)
Celery 芹菜0.635–40 35-4026 (GC, MS) (GC,MS)
Spinach 菠菜0.7–2.2 0.7-2.230–95 30-9526,28 2628 (GC, MS) (GC,MS)
Carrots 胡萝卜1.7∼40 4026 (GC, MS) (GC,MS)
Cabbage 卷心菜1.6∼65 196526 (GC, MS) (GC,MS)
Green pepper 青椒0.2–2.8 0.2-2.810–300 10-30026,28 2628 (GC, MS) (GC,MS)
Mustard 芥末0.6∼9 9∼26,28 2628 (GC, MS) (GC,MS)
Broccoli sprouts 西兰花芽0.154–5 4比526,28 2628 (GC, MS) (GC,MS)
Average value for selected vegetables 选定蔬菜的平均值c1.4 ± 0.950 ± 45
Legumes 豆科植物
Soybeans 大豆0.9∼2 2∼26,28 2628 (GC, MS) (GC,MS)
Broad beans 蚕豆1.8∼20 原文地址: ∼2026 (GC, MS) (GC,MS)
Fava beans 蚕豆1.8∼20 原文地址: ∼2026 (GC, MS) (GC,MS)
Average value for selected legumes 选定豆科植物的平均价值c1.5 ± 0.514 图14 ± 10
Fruits 水果
Tomatoes 西红柿0.9∼5026 (GC, MS) (GC,MS)
Apple 苹果0.6∼12 1226 (GC, MS) (GC,MS)
Banana 香蕉1.3∼15 1526 (GC, MS) (GC,MS)
Kiwi 奇异果2.7∼44 4426 (GC, MS) (GC,MS)
Orange 橙色0.7∼14 1426 (GC, MS) (GC,MS)
Papaya 木瓜2.7∼65 196526 (GC, MS) (GC,MS)
Average value for selected fruits 选定水果的平均值c1.4 ± 1.033 图33 ± 22
Other Foods 其他食物
Bread 面包0.93–4 3-426 (GC, MS) (GC,MS)
Eggs 鸡蛋0.74–5 4比526 (GC, MS) (GC,MS)
Miso 味噌1.7∼7.5 7.526 (GC, MS) (GC,MS)
Fermented bean products (Natto) 发酵豆制品(纳豆)6.1∼30 电话: ∼3026 (GC, MS) (GC,MS)
Average value for selected foods 选定食物的平均值c2.4 ± 2.511 图11 ± 13
Beverages 饮料c
Sake 清酒0.4
Wine 葡萄酒0.6∼5 5∼26 (GC, MS) (GC,MS)
Beer 啤酒0.16∼1 1∼28 (GC, MS) (GC,MS)
Green tea 绿茶2.9, 0.16 2.9,0.1626 (GC, MS) (GC,MS)
Oolong tea 乌龙茶2.726,28 2628 (GC, MS) (GC,MS)
Bovine milk (nonpasteurized, 3.25% fat) 牛奶(未经巴氏杀菌,3.25% 脂肪)∼13 13∼185 18523 (16-channel electrochemical detector) (16通道电化学检测器)
Bovine skim milk powder 牛脱脂奶粉∼0.25 0∼25∼0.75 0.7527 (GC, MS) (GC,MS)
Animal Tissues and Fluids (μg/100 动物组织及液体(克/100) g or 100 mL)d
Human milk 母乳c,ePQQ plus imidazopyrroloquinoline (IPQ): 14–18, 0.14 to 5.5 as IPQ PQQ 联合咪唑吡咯喹啉(IPQ) : 14-18,0.14-5.5为 IPQe31 (HPLC, MS),(HPLC,MS) ,25 (GC, MS) (GC,MS)
Human plasma 人血浆∼0.17, ∼0.33, N.D. 17∼17∼033,N.D.28 (GC, MS), (气相色谱,质谱) ,40(Enzymatic), (酶促反应),
24 (HPLC, Chemical detection) (高效液相色谱,化学检测)
Human spleen 人体脾脏∼0.59 0∼5928 (GC, MS) (GC,MS)
Human pancreas 人类胰腺∼0.4 0.428 (GC, MS) (GC,MS)
Human liver 人类肝脏∼0.1 0∼128 (GC, MS) (GC,MS)
Human adrenal 人类肾上腺∼0.15 0∼1528 (GC, MS) (GC,MS)
Human small intestine 人体小肠∼0.2 0.228 (GC, MS) (GC,MS)
Rat liver 鼠肝∼0.1 0∼128 (GC, MS) (GC,MS)
Rat small intestine 大鼠小肠0.1–0.2 0.1-0.228 (GC, MS) (GC,MS)
Rat testis 老鼠睾丸∼0.09 0∼0928 (GC, MS) (GC,MS)

aAvailable estimates for “free” PQQ in tissues and fluids are limited and variable. In part, this is due to the ability of PQQ to freely combine with amino acids and proteins to form adducts (cf. 组织和体液中“游离” PQQ 的可用估计数量有限且可变。这部分是由于 PQQ 能够自由地与氨基酸和蛋白质结合形成加合物(参见Fig. 13.1 图13.1).bMethodological approaches used for PQQ detection and estimation include gas chromatography (GC) followed by mass spectrometry (MS), high performance/pressure liquid chromatography (HPLC) followed by MS, or separation by solvent partitioning and chromatography followed enzymatic, electrochemical, or chemical approaches designed to be specific for PQQ. 检测和估计 PQQ 的方法学方法包括气相色谱法(GC) ,质谱法(MS) ,高效/高压液相色谱(HPLC) ,质谱(MS) ,或溶剂分配和色谱分离,然后酶法,电化学或化学方法设计专门针对 PQQ 的方法cValues suggest that PQQ is retained in fermented and distilled products to varying degrees. For milk, both bovine and human milk have relatively high concentrations of free PQQ and IPQ, unless processed (i.e., heating and spray drying). 值表明 PQQ 在不同程度的发酵和蒸馏产品中得到保留。对于牛奶,牛奶和人奶中的游离 PQQ 和 IPQ 含量都相对较高,除非经过加工(即加热和喷雾干燥)dAnimal tissues contain about one-tenth the amounts of “free” PQQ as plant tissues. 动物组织中的“游离” PQQ 含量约为植物组织的十分之一eThe ratio of IPQ to PQQ in human milk is 8:1 or greater. Fluid human milk is ∼90% water and provides about 65 母乳中 IPQ 与 PQQ 的比例为8:1或更大。液态母乳含水多达90% ,提供约65 K calories/100 mL.31

For perspective, for mice and rats, about 1 μmole of PQQ per kg of diet is sufficient to ensure optimal growth and development, i.e., equivalent to ∼100 μg/1000 kcal of a mixed diet.2,3 Given that much, if not most, of the PQQ in foods exists as amino acid or protein adducts, an inference, based on the estimates for “free” PQQ in foods (Table 13.1), is that typical diets should be sufficient to meet the apparent PQQ requirement for normal growth and maintenance in animals. Moreover, in human and bovine milk, the total PQQ plus IPQ is ∼200–250 μg per 1000 kcal,18 i.e., there are sufficient PQQ-derived compounds in milk to meet experimental animal requirements. It is also noteworthy that animal tissues contain about one-tenth the amount of “free” PQQ as plant tissues, which also suggests that dietary PQQ can meet the current estimate for sustaining reproduction and growth requirements.26

对于小鼠和大鼠来说,每公斤食物中大约1摩尔的 PQQ 足以确保最佳的生长和发育,即相当于ーー100克/1000千卡的混合饮食。2,3鉴于食物中的 PQQ 大部分(如果不是大部分的话)以氨基酸或蛋白质加合物的形式存在,根据对食物中“游离” PQQ 的估计(表13.1) ,一个推断是典型的饮食应该足以满足动物正常生长和维持的明显 PQQ 需求。此外,在人奶和牛奶中,每1000千卡总的 PQQ 加 IPQ 为ー200ー250克,即牛奶中含有足够的 PQQ 衍生化合物以满足实验动物的需要。还值得注意的是,动物组织中的”游离” PQQ 含量约为植物组织的十分之一,这也表明膳食中的 PQQ 可以满足目前维持生殖和生长需要的估计数

From a physiological perspective, the chemical properties of PQQ are analogous to combining some of the best chemical features of (1) nicotinamide derivatives with reducing potential (e.g., NADH; hydride transfers), (2) ascorbic acid (reducing and antioxidant potential), (3) riboflavin (single electron transfer reactions), and (4) pyridoxal (carbonyl reactivity, carbinolamine adduct formation) into one molecule.8 For example, on a molar basis, PQQ is at least 100 times more efficient than ascorbic acid, menadione, and all the isoflavonoids and polyphenolic compounds tested to date in assays that assess redox cycling potential.8,30 Further, the redox potential for PQQ is compatible to that of effective electron acceptors such as NADH,33,34 ubiquinone,35 ascorbic acid,36 or terminal cytochromes.37With such efficiency and compatibility, PQQ is effective as a redox agent or an antioxidant in vitro at nanomolar to micromolar levels, in contrast to the micromolar to millimolar concentrations usually required for other biofactors.

从生理学的角度来看,PQQ 的化学性质类似于(1)烟酰胺衍生物的一些最佳化学特性与还原电位(例如 NADH; 氢化物转移) ,(2)抗坏血酸(还原和抗氧化电位) ,(3)核黄素(单电子转移反应) ,和(4)吡哆醛(羰基反应,甲醇胺加合物)合成一个分子。8例如,在摩尔基础上,PQQ 的效率至少是抗坏血酸、甲萘醌和所有异黄酮类和多酚类化合物的100倍。8,30此外,PQQ 的氧化还原电位与有效电子受体如 NADH、33,34泛醌、35抗坏血酸、36或末端细胞色素的氧化还原电位相一致。37具有这样的效率和相容性,PQQ 在纳摩尔到微摩尔水平作为氧化还原剂或体外抗氧化剂是有效的,与其他生物因子通常需要的微摩尔到毫摩尔浓度不同。

In this regard, observations made by Akagawa and coworkers34,38 are relevant, i.e., that PQQ can serve as an accessory factor for some PQQ-binding dehydrogenases including l-lactate dehydrogenase (LDH). Although neither PQQ nor PQQH2 is a cofactor for LDH, the presence of PQQ enhanced pyruvate production and inhibited lactate production by LDH in the presence of NADH or NAD+. Moreover, in fibroblast cultures, PQQ exposure reduced the rate of cellular lactate release and caused an increase in intracellular ATP levels along with cellular NAD+ levels. Molecular docking studies indicated PQQ was positioned near the NADH cofactor in the active site pocket of LDH and aided in increasing the rate of electron transfers essential for LDH activity. These novel features of PQQ contribute to possible mechanisms; for example, the redox potential of PQQ is comparable with that of NADH and the locations of the ring nitrogens and hydroquinones within the aromatic planar structure of PQQ allow for rapid tautomerization and lactonization as intermediates in electron transfer reactions. Important to much of the discussion that follows, compounds that modulate the levels of NAD+ are often linked to the potential for enhanced hepatic oxidative metabolism and regulation of signaling molecules, such as those that are critical in the regulation of the sirtuin family of NAD+-dependent protein deacetylases.38–40 Sustaining optimal NAD+ as a coenzyme in most metabolic pathways improves metabolic efficiency.

在这方面,Akagawa 和同事们的观察结果34,38是相关的,也就是说,PQQ 可以作为包括 L-乳酸脱氢酶在内的一些 PQQ 结合脱氢酶的附属因子。虽然 PQQ 和 PQQH2都不是乳酸脱氢酶的辅助因子,但 PQQ 的存在促进了乳酸的合成,并且在 NADH 和 NAD + 存在时抑制乳酸的合成。此外,在成纤维细胞培养中,PQQ 的暴露降低了细胞乳酸的释放速率,并导致细胞内 ATP 水平和 NAD + 水平的升高。分子对接研究表明,PQQ 位于 LDH 活性位点囊区 NADH 辅助因子附近,有助于提高 LDH 活性所必需的电子转移速率。PQQ 的这些新颖特性有助于可能的机制; 例如,PQQ 的氧化还原电位与 NADH 的氧化还原电位相当,而且 PQQ 芳香平面结构中的环亚硝基和氢醌的位置允许作为电子转移反应中的中间体的快速互变异构化和内酯化。调节 NAD + 水平的化合物通常与增强肝唿吸作用和调节信号分子的潜力有关,例如那些在调节 NAD + 依赖蛋白质去乙酰化酶家族中的 sirtuin 家族中起关键作用的化合物。


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