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Does the intestinal microflora synthesize pyrroloquinoline quinone?

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Abstract

Pyrroloquinoline quinone (PQQ) functions as a cofactor for prokaryotic oxidoreductases, such as methanol dehydrogenase and glucose dehydrogenase. When chemically-defined diets without PQQ are fed to animals, lathyritic changes are observed. In previous studies, it was assumed that PQQ was produced by the intestinal microflora; consequently, antibiotics were routinely added to diets. In the present study this assumption is tested further in mice by: (i) examining the effects of dietary antibiotics on fecal PQQ excretion, (ii) isolating the intestinal flora to identify bacteria known to synthesize PQQ and (iii) determining in vitro if the intestinal microflora synthesizes PQQ from radio-chemically labeled precursors. The results of these experiments indicate that little if any PQQ is synthesized by the intestinal microflora. Rather, when PQQ is present in the intestine, the diet is a more obvious source.
... Diet is the apparent source of PQQ in animals given that little, if any, PQQ appears to be synthesized by the intestinal microflora (cf., 3. PQQ's role in Prokaryotes and Fungi; [58,59]). In nutritional studies, delayed growth and neonatal development are features in mice and rats fed diets devoid of PQQ ( Figure 4; [60,61]). ...
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Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or conditional vitamins. For example, the absence of PQQ in diets produces a response like a vitamin–related deficiency with recovery upon PQQ repletion in a dose-dependent manner. Moreover, potential health benefits, such as improved metabolic flexibility and immuno-and neuroprotection, are associated with PQQ supplementation. Here, we address PQQ’s role as an enzymatic cofactor or accessory factor and highlight mechanisms underlying PQQ’s actions. We review both large scale and targeted datasets demonstrating that a neonatal or perinatal PQQ deficiency reduces mitochondria content and mitochondrial-related gene expression. Data are reviewed that suggest PQQ’s modulation of lactate acid and perhaps other dehydrogenases enhance NAD+–dependent sirtuin activity, along with the sirtuin targets, such as PGC-1α, NRF-1, NRF-2 and TFAM; thus, mediating mitochondrial functions. Taken together, current observations suggest vitamin-like PQQ has strong potential as a potent therapeutic nutraceutical.
... 19 At present, animals or humans are assumed to obtain PQQ mainly through diet. 20 Although PQQ remains controversial whether it is a vitamin, 21,22 it has gained increasing attention due to a wide variety of its biological activities, such as anti-oxidation, anti-inflammation, reducing tissue injury and so on. 23 PQQ functions are considered to be associated with its ability to modulate cell metabolism as well as mitochondrial function. ...
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Pyrroloquinoline quinone (PQQ) has a variety of biological functions. However, rare attention has been paid to its effects on exercise‐induced damage. Here, we assessed the potential protective effects of PQQ against the fatigue and oxidative damage caused by repeated exhaustive exercise, and studied the underlying mechanism. The models for exercise‐induced fatigue were established, and the parameters were measured, including the time to exhaustion (TTE), biochemical indicators, the expression of nuclear factor kappa B (NF‐κB) and inflammatory cytokines and so on. Besides, the mitochondrial function was evaluated by the morphology, membrane potential, respiratory function, adenosine triphosphate (ATP) levels, and the application of the mitochondrial complex I inhibitor. The results demonstrate that PQQ prolongs TTE, causes the decrease in the activity of serum creatine kinase and lactate dehydrogenase, increases the activity of antioxidant enzymes, inhibits the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and diminishes the over expression of NF‐κB (p65) and inflammatory mediators. Furthermore, PQQ preserves normal mitochondrial function. Particularly, PQQ reduces the accumulation of ROS triggered by the mitochondrial complex I inhibitor. These data suggest that PQQ can significantly protect mice from exercise‐induced fatigue and oxidative damage by improving mitochondrial function. These data also suggest that PQQ controls mitochondrial activity through directly affecting the NADH dehydrogenase.
... PQQ is well established as an essential cofactor for bacterial function; however, it is not thought to be produced by gut bacteria. 108 In a series of studies utilizing a probiotic species of E. coli genetically engineered to secrete PQQ, Kumar and coworkers demonstrated that treatment of rodents with this PQQ-secreting probiotic elicited the same effects as did oral administration of PQQ. 67,68,70,76,77,109,110 For example, when 1,2-dimethylhydrazine (DMH; 25 mg/kg) was administered subcutaneously twice weekly for 8 weeks, activity of superoxide dismutase and glutathione peroxidase decreased by ∼35% and catalase decreased by almost 50%. ...
... The beneficial effects of PQQ may be associated with the presence of PQQ (at trace levels) in human tissues and body fluids [17][18][19][20][21]. Because eukaryotic cells cannot synthesize PQQ a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 [22], foods have been said to be the only source of PQQ for humans [23,24]. However, the distribution of PQQ in foods is still unclear, mainly due to the difficulty in analyzing the compound. ...
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Pyrroloquinoline quinone (PQQ) is believed to be a new B vitamin-like compound, and PQQ supplementation has received attention as a possible treatment for diseases including dementia and diabetes. However, the distribution of PQQ in foods is unclear, due to the difficulty in analyzing the compound. Therefore, in this study, enzymatic and LC-MS/MS methods were optimized to enable an accurate analysis of PQQ in foods. The optimized methods were applied to the screening of foods, in which PQQ contents were identified in ng/g or ng/mL levels. Furthermore, we newly found that some foods related to acetic acid bacteria contain PQQ at 1.94~5.59 ng/mL higher than beer, which is known to contain relatively high amounts of PQQ. These results suggest that the optimized methods are effective for the screening of foods containing PQQ. Such foods with high PQQ content may be valuable as functional foods effective towards the treatment of certain diseases.
... 32,34) PqqC is the most characterized and has been shown to catalyze the eight-electron oxidation and ring cyclization of AHQQ to form PQQ. 35) A large number of bacteria extracellularly excrete PQQ and is indicated as micrograms per mL of broth culture. 36) On the other hand, common strains of bacteria in the human intestinal tract appear to synthesize little PQQ, 37,38) and hence, it seems that dietary intake is the major source of PQQ in the human body. ...
Article
Pyrroloquinoline quinone (PQQ), an aromatic tricyclic o-quinone, was identified initially as a redox cofactor for bacterial dehydrogenases. Although PQQ is not biosynthesized in mammals, trace amounts of PQQ have been found in human and rat tissues because of its wide distribution in dietary sources. Importantly, nutritional studies in rodents have revealed that PQQ deficiency exhibits diverse systemic responses, including growth impairment, immune dysfunction, and abnormal reproductive performance. Although PQQ is not currently classified as a vitamin, PQQ has been implicated as an important nutrient in mammals. In recent years, PQQ has been receiving much attention owing to its physiological importance and pharmacological effects. In this article, we review the potential health benefits of PQQ with a focus on its growth-promoting activity, anti-diabetic effect, anti-oxidative action, and neuroprotective function. Additionally, we provide an update of its basic pharmacokinetics and safety information in oral ingestion.
... However, PQQ is not synthesized by humans or human gut microbiome. According to Smidt et al. (1991) there is very little if any PQQ is synthesized by intestinal microflora therefore diet is an evident source of PQQ in the gut. Rodents fed with PQQ deficient diet exhibit developmental abnormalities and compromised immune defence (Killgore et al., 1989;Steihberg et al., 1994;Rucker et al., 2009) indicating nutritional importance of PQQ. ...
Article
Ageing involves oxidative stress mediated by Reactive Oxygen Species (ROS) and mitochondrial dysfunction. The present work demonstrates the protective effect of PQQ producing EcN against rotenone induced mitochondrial oxidative stress and consequence of mitochondrial and cellular dysfunction in naturally ageing rat model. PQQ is a potent antioxidant molecule also known to stimulate mitochondrial biogenesis and function in mammals. Firstly, adult rats (16-18weeks old) were treated with rotenone (2.5mg/kg body weight; i.p.) daily for 28days along with PQQ (10mg/kg diet, daily) and modified probiotic EcN strains (10(8)CFU twice weekly). Secondly, ageing rats (48-50weeks old) were gavaged with probiotic EcN strains (10(8)CFU twice weekly) and PQQ (10mg/kg diet, daily) for 8months. PQQ producing EcN-5 treatment prevented rotenone induced hepatic oxidative stress and mitochondrial damage in rats as assessed by reduced lipid peroxidation (29%), elevated glutathione (GSH) content (43%), increased catalase (52%) and superoxide dismutase (52%) activities when compared to only rotenone treatment. Moreover, increased hepatic mitochondrial content (41%), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) mRNA (25%) and mitochondrial Superoxide Dismutase (Mit-SOD) activity (94%) were also observed in EcN-5 treated rats. Rotenone treated rats did not exhibit gain in body weight, whereas rats co-treated with EcN-5 showed significant restoration in body weight gain. Furthermore, weekly administration of EcN-5 to naturally ageing rats for eight months resulted in significant reduction of oxidative stress in hepatic and colonic tissues (assessed by lipid peroxidation, GSH content and catalase and SOD enzyme activities) along with increase in hepatic mitochondrial enzyme activities (Mit-SOD and succinate dehydrogenase) and biogenesis, when compared to untreated rats. Additionally, these rats also exhibited reduced expression of fatty acid synthase (50%) and increased expression of acyl coenzyme oxidase (225%) genes in liver in contrast to untreated rats resulting in lowered triglyceride (13% & 13.5%) and cholesterol (21% & 27%) levels in plasma and liver, respectively. Increased levels of butyrate (93%), propionate (45%) and acetate (18%) were also found in colonic content of these rats. PQQ administered daily (supplemented in diet) exhibited more or less similar effect as weekly gavaged EcN-5 in both the experiments, which substantiate that these effects are mediated by PQQ. These results suggest that genetically modified EcN-5 can be used as a nutritional supplement which can reduce age related oxidative stress and hyperlipidemia. Furthermore, it also rejuvenates healthy mitochondria by stimulating mitochondrial biogenesis and metabolism. Copyright © 2015. Published by Elsevier Inc.
... Accordingly, dietary PQQ appears sufficient to maintain nanomolar concentrations in animal tissues, measured as the parent compound [18]. Organisms common to the gut do not produce PQQ in amounts that are easily determined [21]. Moreover, the levels of PQQ in animal tissues are responsive to changes in diet [5][6][7][8][9][10]. ...
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Pyrroloquinoline quinone (PQQ) influences energy-related metabolism and neurologic functions in animals. The mechanism of action involves interactions with cell signaling pathways and mitochondrial function. However, little is known about the response to PQQ in humans. Using a crossover study design, 10 subjects (5 females, 5 males) ingested PQQ added to a fruit-flavored drink in two separate studies. In study 1, PQQ was given in a single dose (0.2 mg PQQ/kg). Multiple measurements of plasma and urine PQQ levels and changes in antioxidant potential [based on total peroxyl radical-trapping potential and thiobarbituric acid reactive product (TBAR) assays] were made throughout the period of 48 h. In study 2, PQQ was administered as a daily dose (0.3 mg PQQ/kg). After 76 h, measurements included indices of inflammation [plasma C-reactive protein, interleukin (IL)-6 levels], standard clinical indices (e.g., cholesterol, glucose, high-density lipoprotein, low-density lipoprotein, triglycerides, etc.) and (1)H-nuclear magnetic resonance estimates of urinary metabolites related in part to oxidative metabolism. The standard clinical indices were normal and not altered by PQQ supplementation. However, dietary PQQ exposure (Study 1) resulted in apparent changes in antioxidant potential based on malonaldehyde-related TBAR assessments. In Study 2, PQQ supplementation resulted in significant decreases in the levels of plasma C-reactive protein, IL-6 and urinary methylated amines such as trimethylamine N-oxide, and changes in urinary metabolites consistent with enhanced mitochondria-related functions. The data are among the first to link systemic effects of PQQ in animals to corresponding effects in humans.
... Short-term depletion was achieved by switching PQQ+ rats to the PQQ− diet for 48 h. On the basis of previous observations [28,29], the depletion study was conducted for 48 h to allow a washout period for presumed cellular reserves of PQQ. An additional group of rats (n=6) fed a standard LC (laboratory chow) diet was used as a reference. ...
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PQQ (pyrroloquinoline quinone) improves energy utilization and reproductive performance when added to rodent diets devoid of PQQ. In the present paper we describe changes in gene expression patterns and transcriptional networks that respond to dietary PQQ restriction or pharmacological administration. Rats were fed diets either deficient in PQQ (PQQ-) or supplemented with PQQ (approx. 6 nmol of PQQ/g of food; PQQ+). In addition, groups of rats were either repleted by administering PQQ to PQQ- rats (1.5 mg of PQQ intraperitoneal/kg of body weight at 12 h intervals for 36 h; PQQ-/+) or partially depleted by feeding the PQQ- diet to PQQ+ rats for 48 h (PQQ+/-). RNA extracted from liver and a Codelink(R) UniSet Rat I Bioarray system were used to assess gene transcript expression. Of the approx. 10000 rat sequences and control probes analysed, 238 were altered at the P<0.01 level by feeding on the PQQ- diet for 10 weeks. Short-term PQQ depletion resulted in changes in 438 transcripts (P<0.01). PQQ repletion reversed the changes in transcript expression caused by PQQ deficiency and resulted in an alteration of 847 of the total transcripts examined (P<0.01). Genes important for cellular stress (e.g. thioredoxin), mitochondriogenesis, cell signalling [JAK (Janus kinase)/STAT (signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) pathways] and transport were most affected. qRT-PCR (quantitative real-time PCR) and functional assays aided in validating such processes as principal targets. Collectively, the results provide a mechanistic basis for previous functional observations associated with PQQ deficiency or PQQ administered in pharmacological amounts.
Article
Key teaching points: • Endurance exercise training enables skeletal muscle adaptations that can induce increases in mitochondrial biogenesis, improve oxidative capacity, mitochondrial density, and mitochondrial function.• Pyrroloquinoline quinone (PQQ) has been identified as a novel supplement that is involved in physiological processes including redox modulation, cellular energy metabolism, mitochondrial biogenesis, and antioxidant potential.• There is emerging evidence to support that PQQ supplementation can upregulate the molecular signaling responses indicative of mitochondrial biogenesis within skeletal muscle.• If both endurance exercise and PQQ supplementation can elicit increases in the molecular responses indicative of mitochondrial biogenesis, it is possible that both PQQ and exercise may instigate a synergistic ergogenic response.• There is a scarcity of research exploring the possible role of PQQ supplementation with concomitant endurance exercise. Therefore, future research is necessary to investigate the ergogenic potential behind PQQ supplementation in conjunction with endurance exercise.
Chapter
0-quinone cofactors derived from tyrosine and tryptophan are involved in biological reactions that range from oxidative deaminations to free-radical-related redox reactions. Among these cofactors, pyrroloquinoline quinone (PQQ) has excited interest because of its presence in foods, unusual chemical properties and role as a growth-promoting factor in animals. Oral supplementation of PQQ in the nmol/g-diet range has been shown to improve B- and T-cell responsiveness to mitogens, mitochondrial function and reproductive outcome in mice. PQQ is easily absorbed and efficiently taken up by cultured cells. Consequently, a case can be made that PQQ may have physiological importance in animals.
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