Untitled Document

Abstract

Pyrroloquinoline Quinone (PQQ) is a redox-active quinone molecule with significant implications for human health. Originally identified as a bacterial cofactor, PQQ has since been lauded for its diverse biological and therapeutic activities.

1. It serves as an essential cofactor for oxidative enzymes that are vital for mitochondrial function and ATP synthesis.
2. PQQ exhibits superior antioxidant properties that protect against ROS-mediated oxidative stress, aging, neurodegenerative diseases, certain cancers, diabetes, and metabolic disorders. It also enhances cognitive abilities and reduces insulin sensitivity. PQQ's antioxidant nature helps mitigate oxidative stress, which is implicated in many diseases. It has been shown to target cancer cells selectively, suggesting its potential as a therapeutic agent. Clinical studies have indicated the potential benefits of PQQ supplementation, including improvements in cardiovascular health, cognitive function, weight management, insulin sensitivity, and the prevention of metabolic syndromes. The safety of PQQ has been established, with no reported toxicity or genotoxicity in various studies, and it is considered a safe nutritional supplement. Future research directions should focus on determining the optimal dosages of PQQ for specific health outcomes and assessing its long-term effectiveness and safety. The translation of PQQ research into clinical practice could offer new strategies for managing metabolic disorders, enhancing cognitive health, and potentially extending lifespan. In summary, PQQ is a promising molecule with broad potential health benefits, impacting human health from cellular metabolism to disease prevention and treatment, positioning it as a key player in nutritional science and public health.
My comments
This has many characteristics of of such reviews stating many things that are guesses or assumptions as if they are established facts.
1. No mitochondrial PQQ-dependent enzymes are known in mammalian systems. UNTRUE
2. Its antoxidant properties might do this but i know of no evidence in humans.

HOME.	PQQ [Pyrroloquinoline Quinone] Discovery; bacterial enzymes; its role in higher organsims; nutritional aspects Return to my main Science page Return to My Research page Return to Bad Science page			First described by Hauge, and by Anthony and Zatman in 1964
HOME.		PQQ	Jens Hauge and Chris Anthony		Len Zatman

	Early history of PQQ Function and structures of quinoprotein enzymes PQQ and higher organisms, especially man

.............	Early history of PQQ
	A prosthetic group is the part of an enzyme at the active site that is not the protein such as FAD (a riboflavin derivative) as in succinate dehdrogenase. PQQ was first described in 1964 as the prosthetic group of a soluble bacterial glucose dehydrogenase by Hauge (pdf) and as the prosthetic group of a bacterial methanol dehydrogenase by Anthony & Zatman (pdf). I was Len Zatmans's research student. Hauge did no further work on this but it occupied the rest of my carreer. Very soon after our desription a Japanese group (Ameyama and colleagues in Yamaguchi) used our methods to show that the well-known mysterious alcohol dehydrogenase in Acetic acid bacteria has the same novel prosthetic gropup. For my review of these enzymes Click Here Hans Duine and Hans Frank in Delft then showed that two types of glucose dehydrogenase have this novel prosthetic group and they showed that it has an orthoquinone structure and so suggested that all these enzymes should be called Quinoproteins. Other novel prosthetic groups with ortho quinone prosthetic groups have been described and all are now called quinoproteins. The 1st International Symposium on PQQ and Quinoprteins was held in Delft in 1988 and the 5th in Southampton in 2002. Many of the photographs are from these symposia. The structure of PQQ was published 15 years after its first description by Olga Kennard's group in Cambridge.
		The Yamaguchi group: Matsushita ?Urakami? Ameyama and Adachi. This group have continued working on bacterial PQQ Enzymes.	References to this history Full details of all this science are elsewhere on this website together with links to PDFs: Click here

TOP.....	Basic information on function and structures of quinoprotein enzymes Methanol dehydrogenase has a beta propeller structure and a small helical subunit. Memrane Gluscose dehydrogenase has the propeller structre plus a membrane domain that holds it in the membrane; the soluble glucose dehydrogenase has a rare 6-membered ring stucture. The alcohol dehydrogenase has the propeller structure plus a membrane domain and a haem-conataining domain. For full descriptions on this website of the PQQ-containing quinoproteins that are described below Click Here
	The Methanol dehydrogenase of methylotrophic bacteria. This oxidises methanol to formaldehyde during bacterial growth on methane or methanol. It is a soluble enzyme, located in the periplasm. It has a 'propeller' structure with 8 beta sheets forming the propellers. It has a unique 8-membered ring made by formation of a disulphide bridge between adjacent cystein residues in the polypetide chain. There is a calcium ion bonded to PQQ in the active site. This structure was determed by my collaborator, Meenakshi Ghosh.
	The membrane Glucose Dehydrogenase of enteric bacteria, acetic acid bacteria and pseudomonads. This quinoprotein is responsible for oxidation of glucose to gluconic acid in enteric bacteria, acetic acid bacteria and pseudomonads. It is anchored in the periplasmic membrane by the C-terminal domain made up of 5 membrane-spanning helices. the reaction is catalysed in the periplasm by the N-terminal domain; the amino acid sequence of this domain is sufficiently similar to that of methanol dehydrogenase (MDH) for its structure to be modelled using the MDH X-ray coordinates.
	This was the work of my student Gyles Cozier	Structure based on the structure of methanol dehydrogenase.	The special disulphide ring of MDH is replaced with histidine

	The glucose dehydrogenase of Acinetobacter calcoaceticus. This soluble ezyme is the enzyme from which. Hauge first isolated PQQ. It is unusuall in having only 6 propeller blades.

	The Alcohol Dehdrogenase (ADH) of acetic acid bacteria The ADH of Acetobacter aceti is a membrane enzyme responsible for the first step in oxidation of ethanol to acetic acid. The reaction occurs in the periplasm. It has a haem-containing domain and so is a quinohaemoprotein. The basic superbarrel structure and the active-site region are retained, indicating essentially similar mechanisms of action to methanol dehydrogenase. The amino acid sequence of this domain is sufficiently similar to that of methanol dehydrogenase (MDH) for its structure to be modelled using the MDH X-ray coordinates.		Gyles Cozier, who was responsible for all our modelling work
	This was the work of my student Gyles Cozier
	NOTE: A Coprinopsis cinerea (fungus) pyranose dehydrogenase has recently been shown by Takeda et al (pdf) to have PQQ in its crystal structure. It has a 6-membered propeller structure like the soluble glucose dehdyrogenase from which ens Hauge first isolated PQQ
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	Later discussions of the role of PQQ in higher organisms
TOP...	Introduction	Reasons why this work is difficult to evaluate and interpret	Potential Physiological Importance of PQQ	Evaluation of PQQ as a nutritional supplement
	Marketing of PQQ as a nutritional supplement	Dreadful 'interpretation' of work suggesting PQQ has a function related to mitochondria	Recent review in Current Food Science	Healthline: a typical site for nutritional supplements
	PQQ available on Amazon	WEB MD	'Evidence' and criticism from AI search

..........	Introduction Much of the work on the possible role(s) of PQQ in mammalian systems has been driven, or at least affected by the hope of getting evidence for its importance as a nutritional supplement. This has often been funded by companies with a financial interest in this. An important first contribution to this was one of the few contributions on this subect at the 1st International Symposium on PQQ and Quinoproteins in Delft in 1988. This described a positive effect of PQQ on growth of mice that were raised germ-free. This contribution was by Dr R. Rucker who has been perhaps the most important contributor to this subject ever since. These contributions are an attempt to provide information from good sources on the subject and to give some illustrations of misleading and exaggerated claims for PQQ in Mammalian systems.	Reasons why this work is difficult to evaluate and interpret 1. The chemical nature of PQQ. It can exist in 3 redox forms: oxidised quinone, reduced quinol, and half reduced free radical. It is thus a powerful anti-oxidant and it can act as in intermediate in recycling systems. These properties can lead to interesting observations which may or may not have physiological significance. 2. Because of its chemical structure it is able to readily bind to a wide range of molecules and can in effect act as a drug rather than a component in a physiological process. 3. Much of the work on PQQ and mammalian systems has been necessaarily using cell lines or animal models so there is alays the problem of transfer of conclusions or models to whole animals. 4. For final 'proof' tests (sometimes clinical) must be done on human populations (difficult to get permission and expensive)
TOP of Later	Potential Physiological Importance of Pyrroloquinoline Quinone By Robert Rucker et al. Alternative Medicine Review Volume 14, Number 3 2009 Abstract Pyrroloquinoline quinone (PQQ) is a novel biofactor for which a proposition can be made for physiological importance. PQQ was first recognized as an enzyme cofactor in bacteria. It has recently been tentatively identified as a component of interstellar dust. Thus, PQQ may have been present throughout early biological conception and evolution. PQQ is also a potent plant growth factor. Consequently, for animals and humans, there has been constant exposure to PQQ. In animals, PQQ is reported to participate in a range of biological functions with apparent survival benefits (e.g., improved neonatal growth and reproductive performance). There are also benefits from PQQ supplementation related to cognitive, immune, and antioxidant functions, as well as protection from cardiac and neurological ischemic events. Although PQQ is not currently viewed as a vitamin, its involvement in cell signaling pathways, particularly those important to mitochondriogenesis in experimental animal models, may eventually provide a rationale for defining PQQ as vital to life. For humans, such evidence suggests there may be similar parallels or benefits from improving PQQ status. (Altern Med Rev 2009;14(3):268-277) TOP	Evaluation of PQQ as a nutritional supplement on Examine website This website provides a summary plus links to all its sources Summary PQQ is a small molecule once thought to be a vitamin, although its actions in the human body are not related to this hypothesized vitamin-like mechanism. Via its actions as a REDOX agent in cells, it can modify signalling and is thought to support mitochondrial function. PQQ is a small quinone molecule which has the ability to be a REDOX agent, capable of reducing oxidants (an antioxidant effect) and then being recycled by glutathione back into an active form. It appears to be quite stable as it can undergo several thousand cycles before being used up, and it is novel since it associates with protein structures inside the cell (some antioxidants, mostly notably carotenoids like β-carotene and astaxanthin, are located at specific areas of a cell where they exert proportionally more antioxidant effects due to proximity; PQQ seems to do this near proteins like carotenoids do so at the cell membrane). The aforementioned REDOX functions can alter protein function and signalling pathways, and while there is a lot of promising in vitro (outside of a living model) research on what it could do there are only a few promising results of PQQ supplementation, mostly related to either altering some signalling pathways or via its benefits to mitochondria (producing more of them and increasing their efficiency). It is a coenzyme in bacteria (so, to bacteria, this would be something like a B-vitamin) but this role does not appear to extend to humans. Since this does not extend to humans, the designation of PQQ as a vitamin compound has fallen through and it is only considered 'vitamin-like' at best.
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	The marketing of PQQ as a nutritional supplement PQQ is now marketed widely as a supplement with claims for a wide range of benefits. These claims are based on many nutritional investigations of PQQ and many studies on the effect of PQQ in isolated cells or tissues or whole experimental animals (mice and rats). The website claims of the marketers are often factually incorrect, wildly exaggerated and have many misunderstandings about biochemistry and physiology. For unbiased examination of supplements I strongly recommend the website Examine.com which is an "independent organization that presents un-biased research on supplements and nutrition. We currently have over 25000 references to scientific papers". This is an excellent website that examines claims for nutritional supplements and has a lengthy valuable discussion of PQQ.
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	The 5th PQQ Symposium by then merged with B6 Symposium. This fusion was bought about when it was shown that the prosthetic group of amine oxidases is also an orthoquinone (but not PQQ)

....TOP TOP of Later	Dreadful 'interpretation' of work suggesting PQQ has a function related to mitochondria I am writing this response at some length. The same responses are relevant to many PQQ sellers
	PQQ and health. Response to an article in Life Extension Magazine Feb 2011 "Generate Fresh Mitochondria with PQQ. Scientists Discover the “Other CoQ10”. By Perry Marcone. Link to the original article The article quotes important work by Rucker and colleagues (see above) . In early studies, he showed that germ-free mice fed chemically-defined diets thrived more if provided with PQQ. He has been at the forefront of this sort of work and his paper relating PQQ to mitochondrial genesis is the one quoted by the article in Life Extension. We should note that this paper studied the effect of PQQ on isolated cell cultures of mouse liver cells. It requires a lot of extrapolation to conclude that PQQ may have an effect on mitochondrial generation in humans and even more to conclude that PQQ as a nutritional supplement will have an effect on ageing. But of course it may achieve this. It should be remembered that even if PQQ does have such effects this is not evidence that it has a ‘normal’ role in human physiology – it is possibly only acting as a ‘drug’. By its chemical nature it reacts powerfully with free radicals and so is an antioxidant. [Also note that there is no evidence that antioxidants in the diet have any benefit at all]. Some specific comments on the article: The paragraphs in italics are taken direct from the article, given in the order in which they appeared. 1. The most exciting revelation on PQQ emerged early in 2010, when researchers found it not only protected mitochondria from oxidative damage—it stimulated growth of fresh mitochondria! This refers to the Rucker study which used liver cells in tissue culture. This is important interesting work but it does not show that dietary supplementation with PQQ in animals/humans will lead to mitochondrial production. 2. Pre-clinical studies reveal that when deprived of dietary PQQ, animals exhibit stunted growth, compromised immunity, impaired reproductive capability, and most importantly, fewer mitochondria in their tissue. Rates of conception, the number of offspring, and survival rates in juvenile animals are also significantly reduced in the absence of PQQ. Introducing PQQ back into the diet reverses these effects, restoring systemic function while simultaneously increasing mitochondrial number and energetic efficiency. Note that to see these effects animals were often reared in extreme unnatural conditions [that is ok as this was the ‘cleanest’ way of showing effects]. Less effect is likely to be seen in animals if given PQQ in normal conditions. This is not surprising because there is a lot of PQQ in many foods, especially if bacteria have been involved in their production; for example vinegar has a lot of PQQ because it is made using bacteria that use a PQQ quinoprotein to oxidise alcohol to the active component of vinegar – acetic acid.	3. As the primary engines of almost all bioenergy production, the mitochondria rank among the physiological structures most vulnerable to destruction from oxidative damage. PQQ’s formidable free radical–scavenging capacity furnishes the mitochondria with superior antioxidant protection. Firstly, we should not confuse mitochondrial activity with regeneration [the subject of Rucker’s paper]. Free radicals are inescapable occasional products of reaction with oxygen in the final step in energy production. We have evolved thus far by avoiding damage by these free radicals which are happily mopped up by mitochondrial enzymes with that sole purpose. There is no reason to think that “superior antioxidant protection” is needed. 4. At the core of this capacity is an extraordinary molecular stability. As a bioactive coenzyme, PQQ actively participates in the energy transfer within the mitochondria that supplies the body with most of its bioenergy (like CoQ10). This is completely untrue. Although it is true that coenzyme Q actively participates in energy transfer within mitochondria,PQQ has not been shown to have any function whatsoever in mitochondria. In bacteria it does have this function. During methanol oxidation for example the first step in energy production is catalysed by a PQQ containing enzyme that is so important that it constitutes 5-10% of the cell’s protein. PQQ enzymes have only been described in bacteria. 5. Unlike other antioxidant compounds, PQQ’s exceptional stability allows it to carry out thousands of these electron transfers without undergoing molecular breakdown. It has been proven especially effective in neutralizing the ubiquitous superoxide and hydroxyl radicals…….. A consistent finding in the scientific literature is that nutrients like PQQ provide more wide-ranging benefits than conventional antioxidants the general public relies on. As mentioned above, PQQ is a powerful antioxidant and it is stable and so of course will ‘neutralise’ free radicals. But there is no evidence that this ability of PQQ can be relevant to health. There is good evidence that antioxidants in the diet have no positive health benefit and may have slight negative effect. This is published as a Cochrane Review. 6. According to the most recent research, “PQQ is 30 to 5,000 times more efficient in sustaining redox cycling (mitochondrial energy production) . . . than other common [antioxidant compounds], e.g. ascorbic acid.” This is terrible. Redox cycling is a chemical process that was proposed as a way of measuring PQQ in a test tube. It not relevant in any way to “mitochondrial energy production”. 7. In a revolutionary advance, an essential coenzyme called pyrroloquinoline quinone or PQQ has been shown to induce mitochondrial biogenesis—the growth of new mitochondria in aging cells! PQQ is not an essential coenzyme in animals [see above]. The studies of PQQ and mitochondrial genesis that stimulated this article were on liver cells in lab culture, NOT ageing cells, or whole animals or humans.
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TOP	A Recent review in Current Food Science
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	Pyrroloquinoline Quinone (PQQ): Its impact on human health and potential benefits: PQQ: Human health impacts and benefits Yan et al. Curr Res Food Sci . 2024 Oct 22:9:100889. doi: 10.1016/j.crfs.2024.100889 Abstract Pyrroloquinoline Quinone (PQQ) is a redox-active quinone molecule with significant implications for human health. Originally identified as a bacterial cofactor, PQQ has since been lauded for its diverse biological and therapeutic activities. 1. It serves as an essential cofactor for oxidative enzymes that are vital for mitochondrial function and ATP synthesis. 2. PQQ exhibits superior antioxidant properties that protect against ROS-mediated oxidative stress, aging, neurodegenerative diseases, certain cancers, diabetes, and metabolic disorders. It also enhances cognitive abilities and reduces insulin sensitivity. PQQ's antioxidant nature helps mitigate oxidative stress, which is implicated in many diseases. It has been shown to target cancer cells selectively, suggesting its potential as a therapeutic agent. Clinical studies have indicated the potential benefits of PQQ supplementation, including improvements in cardiovascular health, cognitive function, weight management, insulin sensitivity, and the prevention of metabolic syndromes. The safety of PQQ has been established, with no reported toxicity or genotoxicity in various studies, and it is considered a safe nutritional supplement. Future research directions should focus on determining the optimal dosages of PQQ for specific health outcomes and assessing its long-term effectiveness and safety. The translation of PQQ research into clinical practice could offer new strategies for managing metabolic disorders, enhancing cognitive health, and potentially extending lifespan. In summary, PQQ is a promising molecule with broad potential health benefits, impacting human health from cellular metabolism to disease prevention and treatment, positioning it as a key player in nutritional science and public health. My comments This has many characteristics of of such reviews stating many things that are guesses or assumptions as if they are established facts. 1. No mitochondrial PQQ-dependent enzymes are known in mammalian systems. UNTRUE 2. Its antoxidant properties might do this but i know of no evidence in humans.	Healthline: a typical site for nutritional supplements. Website Pyrroloquinoline quinone (PQQ) is found in dark chocolate and green tea. While initial studies show positive effects on health, more research is needed. That said, there’s minimal risk to trying PQQ supplements. PQQ has recently gained a lot of attention in the health and wellness sphere. PQQ supplements are claimed to increase energy levels, mental focus, and longevity, but you may wonder whether there’s any merit to these claims. This article explains everything you need to know about PQQ supplements, including the evidence behind their possible benefits. The bottom line PQQ is a compound that plays a vital role in human health. It’s found in a variety of foods, including dark chocolate and green tea, and PQQ supplements are said to improve brain health, energy levels, and longevity. Yet, current research doesn’t support these benefits. While test-tube and animal studies indicate that PQQ may reduce inflammation and promote mitochondrial health, more research is needed. Although the lack of evidence suggests that there’s no need to supplement with PQQ, the risks of doing so are minimal if you’re interested in trying it.
		WebMD is a prominent American online publisher that provides health, medical news, and well-being information. Founded in 1996, it has grown into one of the most widely visited consumer health websites in the world.
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	PQQ available on Amazon It is remarkable that these sell when there is no real evidence for any benefit (as with many 'nutritional supplements). A personal note: My first isolation of pure PQQ from methanol dehydrogenase took about 4 months: Growth of large amounts of bacteris; purifiation of methanol dehydrogenase; denaturation of my valuable pure enzyme: purification of the PQQ; unknown as PQQ then of course. Final product about 20 tiny red grains of the unknown prosthetic group. I was able to characterise it by its fluorescence.	How it is produced 1. Bacterial Fermentation (Most Common)The vast majority of premium and clinically studied PQQ on the market—such as the widely recognized BioPQQ (sold as MGCPQQ in Europe)—is produced via a natural bacterial fermentation process.The Microorganism: Cultivators utilize specific strains of non-pathogenic, PQQ-producing bacteria, most notably Hyphomicrobium denitrificans. These soil bacteria naturally synthesize PQQ as a byproduct of their metabolic processes.The Process: The bacteria are grown in large, controlled fermentation vats supplied with precise nutrients. As they metabolize, they secrete PQQ.Purification: Once fermentation is complete, the mixture goes through rigorous filtration, separation, and purification steps. The final product is usually synthesized as a pyrroloquinoline quinone disodium salt, reaching a minimum purity of 99.0%. It is then dried into a reddish-brown, water-soluble powder.

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TOP..	Evidence for health benefits summarised on Google search

Pyrroloquinoline Quinone (PQQ): Its impact on human health and potential benefits: PQQ: Human health impacts and benefits

Abstract