Pyrroloquinoline quinone

== History ==

== History ==

It was discovered by Jens Gabriel Hauge in 1964 as the third [[redox cofactor]] after [[nicotinamide]] and [[flavin adenine dinucleotide|flavin]] in bacteria (although he hypothesised that it was [[naphthoquinone]]).<ref>{{Cite journal |last=Hauge JG |year=1964 |title=Glucose dehydrogenase of bacterium anitratum: an enzyme with a novel prosthetic group |journal=J Biol Chem |volume=239 |issue=11 |pages=3630–9 |doi=10.1016/S0021-9258(18)91183-X |pmid=14257587 |doi-access=free}}</ref> Anthony and Zatman also found the unknown redox cofactor in [[alcohol dehydrogenase]]. In 1979, Salisbury and colleagues<ref>{{Cite journal |vauthors=Salisbury SA, Forrest HS, Cruse WB, Kennard O |year=1979 |title=A novel coenzyme from bacterial primary alcohol dehydrogenases |journal=Nature |volume=280 |issue=5725 |pages=843–4 |bibcode=1979Natur.280..843S |doi=10.1038/280843a0 |pmid=471057 |s2cid=3094647}}</ref> as well as Duine and colleagues<ref>{{Cite journal |vauthors=Westerling J, Frank J, Duine JA |year=1979 |title=The prosthetic group of methanol dehydrogenase from Hyphomicrobium X: electron spin resonance evidence for a quinone structure |journal=Biochem Biophys Res Commun |volume=87 |issue=3 |pages=719–24 |doi=10.1016/0006-291X(79)92018-7 |pmid=222269}}</ref> extracted this [[prosthetic group]] from [[methanol dehydrogenase]] of [[methylotroph]]s and identified its molecular structure. Adachi and colleagues discovered that PQQ was also found in ''[[Acetobacter]]''.<ref>{{Cite journal |vauthors=Ameyama M, Matsushita K, Ohno Y, Shinagawa E, Adachi O |year=1981 |title=Existence of a novel prosthetic group, PQQ, in membrane-bound, electron transport chain-linked, primary dehydrogenases of oxidative bacteria |journal=FEBS Lett |volume=130 |issue=2 |pages=179–83 |doi=10.1016/0014-5793(81)81114-3 |pmid=6793395 |doi-access=free|bibcode=1981FEBSL.130..179A }}</ref>

It was discovered by Jens Gabriel Hauge in 1964 as the third [[redox cofactor]] after [[nicotinamide]] and [[flavin adenine dinucleotide|flavin]] in bacteria (although he hypothesised that it was [[naphthoquinone]]).<ref>{{Cite journal |last=Hauge JG |year=1964 |title=Glucose dehydrogenase of bacterium anitratum: an enzyme with a novel prosthetic group |journal=J Biol Chem |volume=239 |issue=11 |pages=3630–9 |doi=10.1016/S0021-9258(18)91183-X |pmid=14257587 |doi-access=free}}</ref> Anthony and Zatman also found the unknown redox cofactor in [[alcohol dehydrogenase]]. In 1979, Salisbury and colleagues<ref>{{Cite journal |vauthors=Salisbury SA, Forrest HS, Cruse WB, Kennard O |year=1979 |title=A novel coenzyme from bacterial primary alcohol dehydrogenases |journal=Nature |volume=280 |issue=5725 |pages=843–4 |bibcode=1979Natur.280..843S |doi=10.1038/280843a0 |pmid=471057 |s2cid=3094647}}</ref> as well as Duine and colleagues<ref>{{Cite journal |vauthors=Westerling J, Frank J, Duine JA |year=1979 |title=The prosthetic group of methanol dehydrogenase from Hyphomicrobium X: electron spin resonance evidence for a quinone structure |journal=Biochem Biophys Res Commun |volume=87 |issue=3 |pages=719–24 |doi=10.1016/0006-291X(79)92018-7 |pmid=222269|bibcode=1979BBRC...87..719W }}</ref> extracted this [[prosthetic group]] from [[methanol dehydrogenase]] of [[methylotroph]]s and identified its molecular structure. Adachi and colleagues discovered that PQQ was also found in ''[[Acetobacter]]''.<ref>{{Cite journal |vauthors=Ameyama M, Matsushita K, Ohno Y, Shinagawa E, Adachi O |year=1981 |title=Existence of a novel prosthetic group, PQQ, in membrane-bound, electron transport chain-linked, primary dehydrogenases of oxidative bacteria |journal=FEBS Lett |volume=130 |issue=2 |pages=179–83 |doi=10.1016/0014-5793(81)81114-3 |pmid=6793395 |doi-access=free|bibcode=1981FEBSL.130..179A }}</ref>

== Biosynthesis ==

== Biosynthesis ==

A novel aspect of PQQ is its biosynthesis in bacteria from a ribosomally translated precursor peptide, PqqA ([[UniProt]] {{UniProt|P27532}}).<ref name="pmid1310505">{{Cite journal |vauthors=Goosen N, Huinen RG, van de Putte P |year=1992 |title=A 24-amino-acid polypeptide is essential for the biosynthesis of the coenzyme pyrrolo-quinoline-quinone. |journal=J Bacteriol |volume=174 |issue=4 |pages=1426–7 |doi=10.1128/jb.174.4.1426-1427.1992 |pmc=206443 |pmid=1310505}}</ref> A [[glutamic acid]] and a [[tyrosine]] in PqqA are cross-linked by the [[radical SAM]] [[enzyme]] PqqE ({{UniProt|P07782}}) with the help of PqqD ({{UniProt|P07781}}) in the first step of PqqA modification.<ref name="pmid21223593" /> A protease then liberates the Glu-Tyr molecule from the peptide backbone. PqqB ({{UniProt|P07779}}) oxidizes the 2 and 3 positions on the tyrosine ring, forming a quinone which quickly becomes AHQQ, finishing the [[pyridine]] ring. PqqC ({{UniProt|P07780}}) then forms the final [[pyrrole]] ring.<ref name="pmid32731194">{{Cite journal |last1=Zhu |first1=W |last2=Klinman |first2=JP |date=December 2020 |title=Biogenesis of the peptide-derived redox cofactor pyrroloquinoline quinone. |journal=Current Opinion in Chemical Biology |volume=59 |pages=93–103 |doi=10.1016/j.cbpa.2020.05.001 |pmc=7736144 |pmid=32731194}}</ref>

A novel aspect of PQQ is its biosynthesis in bacteria from a ribosomally translated precursor peptide, PqqA ([[UniProt]] {{UniProt|P27532}}).<ref name="pmid1310505">{{Cite journal |vauthors=Goosen N, Huinen RG, van de Putte P |year=1992 |title=A 24-amino-acid polypeptide is essential for the biosynthesis of the coenzyme pyrrolo-quinoline-quinone. |journal=J Bacteriol |volume=174 |issue=4 |pages=1426–7 |doi=10.1128/jb.174.4.1426-1427.1992 |pmc=206443 |pmid=1310505}}</ref> A [[glutamic acid]] and a [[tyrosine]] in PqqA are cross-linked by the [[radical SAM]] [[enzyme]] PqqE ({{UniProt|P07782}}) with the help of PqqD ({{UniProt|P07781}}) in the first step of PqqA modification.<ref name="pmid21223593" /> A protease then liberates the Glu-Tyr molecule from the peptide backbone. PqqB ({{UniProt|P07779}}) oxidizes the 2 and 3 positions on the tyrosine ring, forming a quinone which quickly becomes AHQQ, finishing the [[pyridine]] ring. PqqC ({{UniProt|P07780}}) then forms the final [[pyrrole]] ring.<ref name="pmid32731194">{{Cite journal |last1=Zhu |first1=W |last2=Klinman |first2=JP |date=December 2020 |title=Biogenesis of the peptide-derived redox cofactor pyrroloquinoline quinone. |journal=Current Opinion in Chemical Biology |volume=59 |pages=93–103 |doi=10.1016/j.cbpa.2020.05.001 |pmc=7736144 |pmid=32731194}}</ref>

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]], using a [[valine]] and a [[tyrosine]] from the precursor peptide, MftA ({{UniProt|P9WJ81}}).<ref name="pmid21223593">{{Cite journal |last=Haft DH |year=2011 |title=Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners. |journal=BMC Genomics |volume=12 |pages=21 |doi=10.1186/1471-2164-12-21 |pmc=3023750 |pmid=21223593 |doi-access=free }}</ref>

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]], using a [[valine]] and a [[tyrosine]] from the precursor peptide, MftA ({{UniProt|P9WJ81}}).<ref name="pmid21223593">{{Cite journal |last=Haft DH |year=2011 |title=Bioinformatic evidence for a widely distributed, ribosomally produced electron carrier precursor, its maturation proteins, and its nicotinoprotein redox partners. |journal=BMC Genomics |volume=12 |article-number=21 |doi=10.1186/1471-2164-12-21 |pmc=3023750 |pmid=21223593 |doi-access=free }}</ref>

== Role in proteins ==

== Role in proteins ==

Quinoproteins generally embed the cofactor in a unique, six-bladed<ref name="pmid31604769"/> [[beta-barrel]] structure. Some examples also have a [[heme C]] prosthetic group and are termed quinohemoproteins.<ref>{{Cite journal |last1=Matsushita |first1=K |last2=Toyama |first2=H |last3=Yamada |first3=M |last4=Adachi |first4=O |date=January 2002 |title=Quinoproteins: structure, function, and biotechnological applications. |journal=Applied Microbiology and Biotechnology |volume=58 |issue=1 |pages=13–22 |doi=10.1007/s00253-001-0851-1 |pmid=11831471 |s2cid=12469203}}</ref> Although quinoproteins are mostly found in bacteria, a ''[[Coprinopsis cinerea]]'' (fungus) [[pyranose dehydrogenase]] has been shown to use PQQ in its crystal structure.<ref name="pmid31604769">{{Cite journal |last1=Takeda |first1=K |last2=Ishida |first2=T |last3=Yoshida |first3=M |last4=Samejima |first4=M |last5=Ohno |first5=H |last6=Igarashi |first6=K |last7=Nakamura |first7=N |date=15 December 2019 |title=Crystal Structure of the Catalytic and Cytochrome ''b'' Domains in a Eukaryotic Pyrroloquinoline Quinone-Dependent Dehydrogenase. |journal=Applied and Environmental Microbiology |volume=85 |issue=24 |bibcode=2019ApEnM..85E1692T |doi=10.1128/AEM.01692-19 |pmc=6881789 |pmid=31604769 |doi-access=free}}</ref>

Quinoproteins generally embed the cofactor in a unique, six-bladed<ref name="pmid31604769"/> [[beta-barrel]] structure. Some examples also have a [[heme C]] prosthetic group and are termed quinohemoproteins.<ref>{{Cite journal |last1=Matsushita |first1=K |last2=Toyama |first2=H |last3=Yamada |first3=M |last4=Adachi |first4=O |date=January 2002 |title=Quinoproteins: structure, function, and biotechnological applications. |journal=Applied Microbiology and Biotechnology |volume=58 |issue=1 |pages=13–22 |doi=10.1007/s00253-001-0851-1 |pmid=11831471 |s2cid=12469203}}</ref> Although quinoproteins are mostly found in bacteria, a ''[[Coprinopsis cinerea]]'' (fungus) [[pyranose dehydrogenase]] has been shown to use PQQ in its crystal structure.<ref name="pmid31604769">{{Cite journal |last1=Takeda |first1=K |last2=Ishida |first2=T |last3=Yoshida |first3=M |last4=Samejima |first4=M |last5=Ohno |first5=H |last6=Igarashi |first6=K |last7=Nakamura |first7=N |date=15 December 2019 |title=Crystal Structure of the Catalytic and Cytochrome ''b'' Domains in a Eukaryotic Pyrroloquinoline Quinone-Dependent Dehydrogenase. |journal=Applied and Environmental Microbiology |volume=85 |issue=24 |bibcode=2019ApEnM..85E1692T |doi=10.1128/AEM.01692-19 |pmc=6881789 |pmid=31604769 |doi-access=free}}</ref>

PQQ also appears to be essential in some other eukaryotic proteins, albeit not as the direct electron carrier. The mammalian [[lactate dehydrogenase]] requires PQQ to run but uses [[NADH]] as the direct redox cofactor. It seems to speed up the reaction by catalyzing the oxidation of NADH via redox cycling.<ref>{{Cite journal |last1=Akagawa |first1=M |last2=Minematsu |first2=K |last3=Shibata |first3=T |last4=Kondo |first4=T |last5=Ishii |first5=T |last6=Uchida |first6=K |date=27 May 2016 |title=Identification of lactate dehydrogenase as a mammalian pyrroloquinoline quinone (PQQ)-binding protein. |journal=Scientific Reports |volume=6 |pages=26723 |bibcode=2016NatSR...626723A |doi=10.1038/srep26723 |pmc=4882622 |pmid=27230956}}</ref>

PQQ also appears to be essential in some other eukaryotic proteins, albeit not as the direct electron carrier. The mammalian [[lactate dehydrogenase]] requires PQQ to run but uses [[NADH]] as the direct redox cofactor. It seems to speed up the reaction by catalyzing the oxidation of NADH via redox cycling.<ref>{{Cite journal |last1=Akagawa |first1=M |last2=Minematsu |first2=K |last3=Shibata |first3=T |last4=Kondo |first4=T |last5=Ishii |first5=T |last6=Uchida |first6=K |date=27 May 2016 |title=Identification of lactate dehydrogenase as a mammalian pyrroloquinoline quinone (PQQ)-binding protein. |journal=Scientific Reports |volume=6 |article-number=26723 |bibcode=2016NatSR...626723A |doi=10.1038/srep26723 |pmc=4882622 |pmid=27230956}}</ref>

== Controversy regarding role as vitamin ==

== Controversy regarding role as vitamin ==