Pyrroloquinoline quinone (PQQ), also called methoxatin'','' is a
redox cofactor
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
and
antioxidant
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
. Produced by bacteria, it is found in soil and foods such as
kiwifruit
Kiwifruit (often shortened to kiwi in North American, British and continental European English) or Chinese gooseberry is the edible berry of several species of woody vine
A vine (Latin ''vīnea'' "grapevine", "vineyard", from ''vīnum'' ...
, as well as human
breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
.
Enzymes using PQQ as a redox cofactor are called quinoproteins and play a variety of
redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
roles.
Quinoprotein glucose dehydrogenase is used a glucose sensor in bacteria. PQQ stimulates growth in bacteria. Eukaryote targets, including mammalian
lactate dehydrogenase
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...
, are of more interest to health. It is suggested that PQQ taken as a dietary supplement could promote
mitochondrial biogenesis
Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers. It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leadin ...
via this pathway as well as
PGC-1α
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the ''PPARGC1A'' gene. PPARGC1A is also known as human accelerated region 20 ( HAR20). It may, therefore, have played a key ro ...
.
[
]
History
It was discovered by J.G. Hauge as the third redox cofactor
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
after nicotinamide
Niacinamide or Nicotinamide (NAM) is a form of vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may ...
and flavin in bacteria (although he hypothesised that it was naphthoquinone
Naphthoquinones constitute a class of organic compounds structurally related to naphthalene. Two isomers are common for the parent naphthoquinones:
* 1,2-Naphthoquinone
* 1,4-Naphthoquinone
Natural products
* Alkannin
* Hexahydroxy-1,4-napht ...
). Anthony and Zatman also found the unknown redox cofactor in alcohol dehydrogenase
Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to N ...
. In 1979, Salisbury and colleagues as well as Duine and colleagues extracted this prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
from methanol dehydrogenase
In enzymology, a methanol dehydrogenase is an enzyme that catalyzes the chemical reaction:
:methanol \rightleftharpoons formaldehyde + 2 electrons + 2H+
How the electrons are captured and transported depends upon the kind of methanol dehydrogenas ...
of methylotroph
Methylotrophs are a diverse group of microorganisms that can use reduced one-carbon compounds, such as methanol or methane, as the carbon source for their growth; and multi-carbon compounds that contain no carbon-carbon bonds, such as dimethyl et ...
s and identified its molecular structure. Adachi and colleagues discovered that PQQ was also found in ''Acetobacter
''Acetobacter'' is a genus of acetic acid bacteria. Acetic acid bacteria are characterized by the ability to convert ethanol to acetic acid in the presence of oxygen. Of these, the genus ''Acetobacter'' is distinguished by the ability to oxidize ...
''.
Biosynthesis
A novel aspect of PQQ is its biosynthesis in bacteria from a ribosomally translated precursor peptide, PqqA (UniProt
UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects. It contains a large amount of information about the biological function of proteins derived from ...
). A glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
and a tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
in PqqA are cross-linked by the radical SAM
Radical SAM is a designation for a superfamily of enzymes that use a +_cluster.html" ;"title="Fe-4Ssup>+ cluster">Fe-4Ssup>+ cluster to reductively cleave ''S''-adenosyl-L-methionine (SAM) to generate a radical, usually a 5′- deoxyadenosyl rad ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
PqqE () with the help of PqqD () in the first step of PqqA modification. A protease then liberates the Glu-Tyr molecule from the peptide backbone. PqqB () oxidizes the 2 and 3 positions on the tyrosine ring, forming a quinone which quickly becomes AHQQ, finishing the pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...
ring. PqqC () then forms the final pyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4 H4 NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-meth ...
ring.
Efforts to understand PQQ biosynthesis have contributed to broad interest in radical SAM enzymes and their ability to modify proteins, and an analogous radical SAM enzyme-dependent pathway has since been found that produces the putative electron carrier mycofactocin
Mycofactocin (MFT) is a family of small molecules derived from a peptide of the type known as RiPP (ribosomally synthesized and post-translationally modified peptides), naturally occurring in many types of '' Mycobacterium''. It was discovered in ...
, using a valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
and a tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
from the precursor peptide, MftA ().
Role in proteins
Quinoproteins generally embed the cofactor in a unique, six-bladed beta-barrel
In protein structures, a beta barrel is a beta sheet composed of tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrogen bond). Beta-strands in many beta-barrels are ...
structure. Some examples also have a heme c prosthetic group and are termed quinohemoproteins. Although quinoproteins are mostly found in bacteria, a ''Coprinopsis cinerea
''Coprinopsis cinerea'' is a species of mushroom in the family Psathyrellaceae. Commonly known as the gray shag, it is edible, but must be used promptly after collecting.
''Coprinopsis cinerea'' is an important model organism for studying fun ...
'' (fungus) pyranose dehydrogenase Pyranose is a collective term for saccharides that have a chemical structure that includes a six-membered ring consisting of five carbon atoms and one oxygen atom. There may be other carbons external to the ring. The name derives from its similarity ...
has been shown to use PQQ in its crystal structure.
PQQ also appears to be essential in some other eukaryotic proteins, albeit not as the direct electron carrier. The aforementioned mammalian lactate dehydrogenase
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...
requires PQQ to run, but uses NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
as the direct redox cofactor. It seems to speed up the reaction by catalyzing the oxidation of NADH via redox-cycling.
Controversy regarding role as vitamin
The scientific journal ''Nature'' published the 2003 paper by Kasahara and Kato that essentially stated that PQQ was a new vitamin and in 2005, an article by Anthony and Fenton that stated that the 2003 Kasahara and Kato paper drew incorrect and unsubstantiated conclusions. An article by Bruce Ames
Bruce Nathan Ames (born December 16, 1928) is an American biochemist. He is a professor of Biochemistry and Molecular Biology Emeritus at the University of California, Berkeley, and was a senior scientist at Children's Hospital Oakland Research I ...
in ''The Proceedings of the National Academy of Sciences'' in 2018 identified pyrroloquinoline quinone as a "longevity vitamin" not essential for immediate survival, but necessary for long-term health.
See also
* L-aminoadipate-semialdehyde dehydrogenase
In enzymology, a L-aminoadipate-semialdehyde dehydrogenase () is an enzyme that catalyzes the chemical reaction
:L-2-aminoadipate 6-semialdehyde + NAD(P)+ + H2O \rightleftharpoons L-2-aminoadipate + NAD(P)H + H+
The 4 substrates of this enzyme ...
,
References
{{Enzyme cofactors
Pyrroloquinoline quinone enzymes
Cofactors
Tricarboxylic acids
Nitrogen heterocycles
Heterocyclic compounds with 3 rings