|Jmol-3D images||Image 1|
|Molar mass||330.21 g mol−1|
|Flash point||569.8 °C|
| (what is: / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Pyrroloquinoline quinone (PQQ) was discovered by J.G. Hauge as the third redox cofactor after nicotinamide and flavin in bacteria (although he hypothesised that it was naphthoquinone). Anthony and Zatman also found the unknown redox cofactor in alcohol dehydrogenase and named it methoxatin. In 1979, Salisbury and colleagues as well as Duine and colleagues extracted this prosthetic group from methanol dehydrogenase of methylotrophs and identified its molecular structure. Adachi and colleagues identified that PQQ was also found in Acetobacter.
These enzymes containing PQQ are called quinoproteins. Glucose dehydrogenase, one of the quinoproteins, is used as a glucose sensor. Subsequently, PQQ was found to stimulate growth in bacteria. In addition, antioxidant and neuro-protective effects were also found.
In 2010, researchers at the University of California at Davis released a peer-reviewed publication showing that PQQ’s critical role in growth and development stems from its unique ability to activate cell signaling pathways directly involved in cellular energy metabolism, development, and function.
Most significantly, the study demonstrated that PQQ not only protects mitochondria from oxidative stress—it promotes the spontaneous generation of new mitochondria within aging cells, a process known as mitochondrial biogenesis. The implications of this discovery for human health and longevity are significant because the only other known methods proven to stimulate mitochondiral biogenesis in aging humans are intense aerobic exercise, strict caloric restriction, and certain medications such as thiazolidinediones and the diabetes drug metformin.
Activation of signaling molecules
The team of researchers at the University of California analyzed PQQ’s influence over cell signaling pathways involved in the generation of new mitochondria and found that there are three signaling molecules activated by PQQ that cause cells to undergo spontaneous mitochondrial biogenesis:
- PQQ activates expression of PCG-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), a “master regulator” that mobilizes cells’ response to various external triggers. It directly stimulates genes that promote mitochondrial and cellular respiration, growth, and proliferation. Its capacity to upregulate cellular metabolism at the genetic level favorably affects blood pressure, cholesterol and triglyceride breakdown, and the onset of obesity.
- PQQ triggers the CREB signaling protein (cAMP-response element-binding protein), which plays a pivotal role in embryonic development and growth. It also beneficially interacts with histones, proteins involved in the packaging and nuclear organization of cell DNA. CREB also stimulates the growth of new mitochondria.
- PQQ regulates a recently discovered cell signaling protein called DJ-1. As with PCG-1α and CREB, DJ-1 is involved in cell function and survival, has been shown to prevent cell death by combating intensive oxidative stress, and is likely important to brain health and function. DJ-1 mutations have been conclusively linked to the onset of rare inherited forms of Parkinson’s disease and other neurological disorders.
PQQ is a neuroprotective compound that has been shown in a small number of preliminary studies to protect memory and cognition in aging animals and humans. It has been shown to reverse cognitive impairment caused by chronic oxidative stress in animal models and improve performance on memory tests. PQQ supplementation stimulates the production and release of nerve growth factors in cells that support neurons in the brain, a possible mechanism for the improvement of memory function it appears to produce in aging humans and rats.
PQQ has also been shown to safeguard against the self-oxidation of the DJ-1 protein, an early step in the onset of some forms of Parkinson’s disease.
PQQ protects brain cells against oxidative damage following ischemia-reperfusion injury—the inflammation and oxidative damage that result from the sudden return of blood and nutrients to tissues deprived of them by stroke. Reactive nitrogen species (RNS) arise spontaneously following stroke and spinal cord injuries and impose severe stresses on damaged neurons, contributing to subsequent long-term neurological damage. PQQ suppresses RNS in experimentally induced strokes, and provides additional protection following spinal cord injury by blocking inducible nitric oxide synthase (iNOS), a major source of RNS.
In animal models, administration of PQQ immediately prior to induction of stroke significantly reduces the size of the damaged brain area. These observations have been compounded by the observation in vivo that PQQ protects against the likelihood of severe stroke in an experimental animal model for stroke and brain hypoxia.
PQQ also affects some of the brain’s neurotransmitter systems. It protects neurons by modulating the properties of the N-methyl-D-aspartate (NMDA) receptor, and so reducing excitotoxicity—the damaging consequence of long-term overstimulation of neurons that is associated with many neurodegenerative diseases and seizures.
PQQ also protects the brain against neurotoxicity induced by other powerful toxins, including mercury(a suspected factor in the development of Alzheimer’s disease) and oxidopamine (a potent neurotoxin used by scientists to induce Parkinsonism in laboratory animals by destroying dopaminergic and noradrenergic neurons.)
PQQ prevents aggregation of alpha-synuclein, a protein associated with Parkinson’s disease. PQQ also protects nerve cells from the toxic effects of the amyloid-beta protein linked with Alzheimer’s disease, and reduces the formation of new amyloid beta aggregates.
PQQ has been shown to promote memory, attention, and cognition in laboratory animals.
In humans, in one double-blind, placebo-controlled clinical trial conducted in Japan in 2007, supplementation with 20 mg per day of PQQ resulted in improvements on tests of higher cognitive function in a group of 71 middle-aged and elderly people aged between 40-70, who outperformed the placebo group by more than twofold in their standardized memory tests. Interestingly, co-administration of the unrelated compound coenzyme Q10 (CoQ10) further improved performance on standardized memory tests when subjects also took 300 mg per day of CoQ10. No adverse effects were linked to the supplementation, and the results suggested that PQQ, especially when combined with CoQ10, can be used to improve mental status and quality of life in older patients, and help slow or prevent age-related cognitive decline in middle-age patients.
However, the study was not peer-reviewed and was published in a non-academic journal. No proper scientific study of PQQ effects on memory or cognition in humans has been conducted, as of 2013.
Damage from a heart attack, like a stroke, is inflicted via ischemic reperfusion injury. PQQ administration reduces the size of damaged areas in animal models of acute heart attack (myocardial infarction). Significantly, this occurs irrespective of whether the chemical is given before or after the ischemic event itself, suggesting that administration within the first hours of medical response may offer benefits to heart attack victims.
Researchers at the University of California at San Francisco investigated this potential, comparing PQQ with the beta blocker metoprolol—a standard post-MI clinical treatment. Independently, both treatments reduced the size of the damaged areas and protected against heart muscle dysfunction. When given together, the left ventricle’s pumping pressure was enhanced. The combination of PQQ with metoprolol also increased mitochondrial energy-producing functions—but the effect was modest compared with PQQ alone. Only PQQ favorably reduced lipid peroxidation. These results led the researchers to conclude that “PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage.” 
Subsequent research has also demonstrated that PQQ helps heart muscle cells resist acute oxidative stress by preserving and enhancing mitochondrial function.
Despite its proposed classification as an essential nutrient, no recommended daily intake of PQQ has been established.
Animal studies suggest PQQ supports healthy mitochondrial function at human equivalent doses (H.E.D.) as low as 1.44 milligrams per day, but 3 milligrams per kilogram have been shown to protect rat hearts from ischemic injury. The majority of human studies have used higher doses, of 10–20 mg or more. Consequently, nearly all PQQ sold as supplements in the United States range from 10–20 mg.[unreliable source?]
Although Nature Magazine published the 2003 paper by Kasahara and Kato which essentially stated that PQQ was a new vitamin, they also subsequently published, in 2005, an article by Chris Anthony and his colleague L.M. Fenton of the University of Southhampton which states that the 2003 Kasahara and Kato paper drew incorrect and unsubstantiated conclusions. On his website, Anthony discusses the Nature Magazine publications:
When I pointed out to the journal Nature that their high reputation was being used to justify investments of millions of dollars in the development of PQQ as a vitamin, they investigated the original paper, agreed with our objections and published our argument against it (Felton & Anthony, Nature Vol. 433, 2005). They also published (alongside ours) a paper by Rucker disagreeing with the conclusions of Kasahara and Kato on nutritional grounds, concluding “that insufficient information is available so far to state that PQQ uniquely performs an essential vitamin function in animals”.
Anthony further states on his website that "No mammalian PQQ-containing enzyme (quinoprotein) has been described" and that PQQ therefore cannot be called a "vitamin". The latter statement is an exaggeration, since there are at least four human quinoproteins, the enzyme activity of which is dependent on PQQ:
- serine/threonine-protein kinase/endoribonuclease IRE1 (Inositol-requiring protein 1, involved in unfolded protein response, sequence O75460 in Uniprot),
- flavin reductase (Biliverdin reductase B, P30043 in Uniprot),
- Acyl-CoA synthetase family member 4 (L-aminoadipate-semialdehyde dehydrogenase, Q4L235 in Uniprot) and
- Dopamine beta-hydroxylase (Dopamine beta-monooxygenase, P09172  in Uniprot).
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