Pyrroloquinoline quinone

Pyrroloquinoline quinone
Identifiers
72909-34-3 N
ChEBI CHEBI:18315 YesY
ChemSpider 997 YesY
Jmol interactive 3D Image
KEGG C00113 YesY
MeSH PQQ+Cofactor
PubChem 1024
UNII 47819QGH5L N
Properties
C14H6N2O8
Molar mass 330.21 g·mol−1
Density 1.963 g/cm3
Hazards
Flash point 569.8 °C (1,057.6 °F; 842.9 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

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).[1] Anthony and Zatman also found the unknown redox cofactor in alcohol dehydrogenase and named it methoxatin.[2] In 1979, Salisbury and colleagues[3] as well as Duine and colleagues[4] 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.[5]

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.[6] In addition, antioxidant and neuroprotective effects were also found.[7]

Research in animals

Mitochondrial biogenesis in mice

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. The study demonstrated that PQQ not only protects mouse hepatocyte mitochondria from oxidative stress—it promotes the spontaneous generation of new mitochondria within aging cells, a process known as mitochondrial biogenesis.[8]

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 mouse proteins activated by PQQ that cause cells to undergo spontaneous mitochondrial biogenesis: peroxisome proliferator-activated receptor gamma coactivator 1-alpha, cAMP response element-binding protein, and the DJ-1 protein.[8]

Cardioprotection in rat models

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.[9]

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.” [10]

Subsequent research has also demonstrated that PQQ helps heart muscle cells resist acute oxidative stress by preserving and enhancing mitochondrial function.[11]

Radiation poisoning in mice

In a study of gamma radiation poisoning in mice, 4mg/kg of PQQ improved 30-day survival from 2/20 to 12/20 at an 8 Gy dose.[12]

Neuroprotection

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.[13][14] It has been shown to reverse cognitive impairment caused by chronic oxidative stress in animal models and improve performance on memory tests.[15] PQQ supplementation stimulates the production and release of nerve growth factors in cells that support neurons in the brain,[16] 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.[17]

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.[18] 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.[19] PQQ suppresses RNS in experimentally induced strokes,[20] and provides additional protection following spinal cord injury by blocking inducible nitric oxide synthase (iNOS), a major source of RNS.[21]

In animal models, administration of PQQ immediately prior to induction of stroke significantly reduces the size of the damaged brain area.[22] 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.[18]

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,[23][24] and so reducing excitotoxicity—the damaging consequence of long-term overstimulation of neurons that is associated with many neurodegenerative diseases and seizures.[25][26][27][28]

PQQ also protects the brain against neurotoxicity induced by other powerful toxins, including mercury[29](a suspected factor in the development of Alzheimer's disease[30]) and oxidopamine[31] (a potent neurotoxin used by scientists to induce Parkinsonism in laboratory animals by destroying dopaminergic and noradrenergic neurons.[32])

PQQ prevents aggregation of alpha-synuclein, a protein associated with Parkinson's disease.[33] PQQ also protects nerve cells from the toxic effects of the amyloid-beta protein linked with Alzheimer's disease,[34] and reduces the formation of new amyloid beta aggregates.[35]

Controversy regarding role as vitamin

Although the scientific journal Nature 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 Southampton which states that the 2003 Kasahara and Kato paper drew incorrect and unsubstantiated conclusions.[36] On his website,[37] Anthony discusses the Nature 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 is one mammalian enzyme which appears to use PQQ as a cofactor:[38]

References

  1. ↑ Hauge JG (1964). "Glucose dehydrogenase of bacterium anitratum: an enzyme with a novel prosthetic group". J Biol Chem 239: 3630–9. PMID 14257587.
  2. ↑ Anthony C, Zatman LJ (1967). "The microbial oxidation of methanol. The prosthetic group of the alcohol dehydrogenase of Pseudomonas sp. M27: a new oxidoreductase prosthetic group". Biochem J 104 (3): 960–9. PMC 1271238. PMID 6049934.
  3. ↑ Salisbury SA, Forrest HS, Cruse WB, Kennard O (1979). "A novel coenzyme from bacterial primary alcohol dehydrogenases". Nature 280 (5725): 843–4. doi:10.1038/280843a0. PMID 471057.
  4. ↑ Westerling J, Frank J, Duine JA (1979). "The prosthetic group of methanol dehydrogenase from Hyphomicrobium X: electron spin resonance evidence for a quinone structure". Biochem Biophys Res Commun 87 (3): 719–24. doi:10.1016/0006-291X(79)92018-7. PMID 222269.
  5. ↑ Ameyama M, Matsushita K, Ohno Y, Shinagawa E, Adachi O (1981). "Existence of a novel prosthetic group, PQQ, in membrane-bound, electron transport chain-linked, primary dehydrogenases of oxidative bacteria". FEBS Lett 130 (2): 179–83. doi:10.1016/0014-5793(81)81114-3. PMID 6793395.
  6. ↑ Ameyama M, Matsushita K, Shinagawa E, Hayashi M, Adachi O (1988). "Pyrroloquinoline quinone: excretion by methylotrophs and growth stimulation for microorganisms". BioFactors 1 (1): 51–3. PMID 2855583.
  7. ↑ Rucker R, Chowanadisai W, Nakano M. (2009). "Potential physiological importance of pyrroloquinoline quinone". Altern Med Rev 14 (3): 179–83.
  8. 1 2 Chowanadisai, W.; Bauerly, K. A.; Tchaparian, E.; Wong, A.; Cortopassi, G. A.; Rucker, R. B. (January 2010). "Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression". Journal of Biological Chemistry 285 (1): 142–152. doi:10.1074/jbc.M109.030130. PMC 2804159. PMID 19861415.
  9. ↑ Zhu, B. Q.; Zhou, H. Z.; Teerlink, J. R.; Karliner, J. S. (November 2004). "Pyrroloquinoline quinone (PQQ) decreases myocardial infarct size and improves cardiac function in rat models of ischemia and ischemia/reperfusion". Cardiovascular Drugs and Therapy 18 (6): 421–431. doi:10.1007/s10557-004-6219-x. PMID 15770429.
  10. ↑ Zhu, B. -Q.; Simonis, U.; Cecchini, G.; Zhou, H. -Z.; Li, L.; Teerlink, J. R.; Karliner, J. S. (June 2006). "Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury". Journal of Cardiovascular Pharmacology and Therapeutics 11 (2): 119–128. doi:10.1177/1074248406288757. PMID 16891289.
  11. ↑ Tao, R; Karliner, J; Simonis, U; Zheng, J; Zhang, J; Honbo, N; Alano, C (2007). "Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in adult rat cardiac myocytes". Biochemical and Biophysical Research Communications 363 (2): 257–62. doi:10.1016/j.bbrc.2007.08.041. PMC 2844438. PMID 17880922.
  12. ↑ Xiong, X. H.; Zhao, Y; Ge, X; Yuan, S. J.; Wang, J. H.; Zhi, J. J.; Yang, Y. X.; Du, B. H.; Guo, W. J.; Wang, S. S.; Yang, D. X.; Zhang, W. C. (2011). "Production and radioprotective effects of pyrroloquinoline quinone". International Journal of Molecular Sciences 12 (12): 8913–23. doi:10.3390/ijms12128913. PMC 3257108. PMID 22272111.
  13. ↑ Takatsu, H; Owada, K; Abe, K; Nakano, M; Urano, S (2009). "Effect of vitamin E on learning and memory deficit in aged rats". Journal of nutritional science and vitaminology 55 (5): 389–93. doi:10.3177/jnsv.55.389. PMID 19926923.
  14. ↑ Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. (2009). "Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons". Food Style 21 13 (7): 50–52.
  15. ↑ Ohwada, K.; Takeda, H.; Yamazaki, M.; Isogai, H.; Nakano, M.; Shimomura, M.; Fukui, K.; Urano, S. (January 2008). "Pyrroloquinoline quinone (PQQ) prevents cognitive deficit caused by oxidative stress in rats". Journal of Clinical Biochemistry and Nutrition 42 (1): 29–34. doi:10.3164/jcbn.2008005. PMC 2212345. PMID 18231627.
  16. ↑ Murase, K; Hattori, A; Kohno, M; Hayashi, K (1993). "Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes". Biochemistry and molecular biology international 30 (4): 615–21. PMID 8401318.
  17. ↑ Nunome, K; Miyazaki, S; Nakano, M; Iguchi-Ariga, S; Ariga, H (2008). "Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1". Biological & Pharmaceutical Bulletin 31 (7): 1321–6. doi:10.1248/bpb.31.1321. PMID 18591768.
  18. 1 2 Jensen, FE; Gardner, GJ; Williams, AP; Gallop, PM; Aizenman, E; Rosenberg, PA (1994). "The putative essential nutrient pyrroloquinoline quinone is neuroprotective in a rodent model of hypoxic/ischemic brain injury". Neuroscience 62 (2): 399–406. doi:10.1016/0306-4522(94)90375-1. PMID 7830887.
  19. ↑ Ono, K.; Suzuki, H.; Sawada, M. (2010-10-05). "Delayed neural damage is induced by iNOS-expressing microglia in a brain injury model". Neuroscience Letters 473 (2): 146–150. doi:10.1016/j.neulet.2010.02.041. PMID 20178828.
  20. ↑ Zhang, Y; Rosenberg, PA (2002). "The essential nutrient pyrroloquinoline quinone may act as a neuroprotectant by suppressing peroxynitrite formation". The European Journal of Neuroscience 16 (6): 1015–24. doi:10.1046/j.1460-9568.2002.02169.x. PMID 12383230.
  21. ↑ Hirakawa, A.; Shimizu, K.; Fukumitsu, H.; Furukawa, S. (2009-01-09). "Pyrroloquinoline quinone attenuates iNOS gene expression in the injured spinal cord". Biochemical and Biophysical Research Communications 378 (2): 308–312. doi:10.1016/j.bbrc.2008.11.045. PMID 19026989.
  22. ↑ Zhang, Y.; Feustel, P.; Kimelberg, H. (2006-06-13). "Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat". Brain Research 1094 (1): 200–206. doi:10.1016/j.brainres.2006.03.111. PMID 16709402.
  23. ↑ Aizenman, E; Hartnett, KA; Zhong, C; Gallop, PM; Rosenberg, PA (1992). "Interaction of the putative essential nutrient pyrroloquinoline quinone with the N-methyl-D-aspartate receptor redox modulatory site". Journal of Neuroscience 12 (6): 2362–9. PMID 1318959.
  24. ↑ Aizenman, E; Jensen, FE; Gallop, PM; Rosenberg, PA; Tang, LH (1994). "Further evidence that pyrroloquinoline quinone interacts with the N-methyl-D-aspartate receptor redox site in rat cortical neurons in vitro". Neuroscience Letters 168 (1-2): 189–92. doi:10.1016/0304-3940(94)90447-2. PMID 7518062.
  25. ↑ Scanlon, JM; Aizenman, E; Reynolds, IJ (1997). "Effects of pyrroloquinoline quinone on glutamate-induced production of reactive oxygen species in neurons". European Journal of Pharmacology 326 (1): 67–74. doi:10.1016/S0014-2999(97)00137-4. PMID 9178657.
  26. ↑ Hossain, M. A. (Sep 2005). "Molecular mediators of hypoxic-ischemic injury and implications for epilepsy in the developing brain". Epilepsy & Behavior 7 (2): 204–213. doi:10.1016/j.yebeh.2005.05.015. PMID 16054439.
  27. ↑ Dong, X. X.; Wang, Y.; Qin, Z. H. (April 2009). "Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases". Acta Pharmacologica Sinica 30 (4): 379–387. doi:10.1038/aps.2009.24. PMID 19343058.
  28. ↑ Foran, E.; Trotti, D. (July 2009). "Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis". Antioxidants & Redox Signaling 11 (7): 1587–1602. doi:10.1089/ars.2009.2444. PMC 2842587. PMID 19413484.
  29. ↑ Zhang, P.; Xu, Y.; Sun, J.; Li, X.; Wang, L.; Jin, L. (March 2009). "Protection of pyrroloquinoline quinone against methylmercury-induced neurotoxicity via reducing oxidative stress". Free Radical Research 43 (3): 224–233. doi:10.1080/10715760802677348. PMID 19191107.
  30. ↑ Mutter J, C. A. (2010). "Does inorganic mercury play a role in Alzheimer's disease? A systematic review and an integrated molecular mechanism". Journal of Alzheimer's Disease 22 (2): 357–374. doi:10.3233/JAD-2010-100705. PMID 20847438.
  31. ↑ Hara, H.; Hiramatsu, H.; Adachi, T. (March 2007). "Pyrroloquinoline quinone is a potent neuroprotective nutrient against 6-hydroxydopamine-induced neurotoxicity". Neurochemical Research 32 (3): 489–495. doi:10.1007/s11064-006-9257-x. PMID 17268846.
  32. ↑ Breese, G. R.; Knapp, D. J.; Criswell, H. E.; Moy, S. S.; Papadeas, S. T.; Blake, B. L. (February 2005). "The neonate-6-hydroxydopamine-lesioned rat: a model for clinical neuroscience and neurobiological principles". Brain Research Reviews 48 (1): 57–73. doi:10.1016/j.brainresrev.2004.08.004. PMID 15708628.
  33. ↑ Kobayashi, M.; Kim, J.; Kobayashi, N.; Han, S.; Nakamura, C.; Ikebukuro, K.; Sode, K. (2006-10-27). "Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein". Biochemical and Biophysical Research Communications 349 (3): 1139–1144. doi:10.1016/j.bbrc.2006.08.144. PMID 16962995.
  34. ↑ Zhang, J. J.; Zhang, R. F.; Meng, X. K. (2009-10-30). "Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells". Neuroscience Letters 464 (3): 165–169. doi:10.1016/j.neulet.2009.08.037. PMID 19699263.
  35. ↑ Kim, J.; Kobayashi, M.; Fukuda, M.; Ogasawara, D.; Kobayashi, N.; Han, S.; Nakamura, C.; Inada, M.; Miyaura, C.; Ikebukuro, K.; Sode, K. (2010). "Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins". Prion 4 (1): 26–31. doi:10.4161/pri.4.1.10889. PMC 2850417. PMID 20083898.
  36. ↑ Felton LM, Anthony C (2005). "Biochemistry: role of PQQ as a mammalian enzyme cofactor?". Nature 433 (7025): E10; discussion E11–2. doi:10.1038/nature03322. PMID 15689995.
  37. ↑ Anthony C. "Chris Anthony/My Research". Retrieved 22 April 2012.
  38. ↑ Kasahara T, Kato T (2005). "Biochemistry: Is pyrroloquinoline quinone a vitamin? (Reply)?". Nature 433 (7025): E11–E12. doi:10.1038/nature03324.
  39. ↑ "L-aminoadipate-semialdehyde dehydrogenase (Homo sapiens)". BRENDA. Technische Universität Braunschweig. July 2015. Retrieved 18 July 2015.
  40. ↑ "Pyrroloquinoline quinone (HMDB13636)". Human Metabolome Database. University of Alberta. Retrieved 19 July 2015. Enzymes containing PQQ are called quinoproteins. PQQ and quinoproteins play a role in the redox metabolism and structural integrity of cells and tissues [PMID 2558842]. It was reported that aminoadipate semialdehyde dehydrogenase (AASDH) might also use PQQ as a cofactor, suggesting a possibility that PQQ is a vitamin in mammals. [PMID 12712191].
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