UniProt functional annotation for Q03471



	UniProt functional annotation for Q03471

UniProt code: Q03471.

Organism: Penicillium roqueforti.

Taxonomy: Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.

Function: Aristolochene synthase; part of the gene cluster that mediates the biosynthesis of PR-toxin, a bicyclic sesquiterpene belonging to the eremophilane class and acting as a mycotoxin (PubMed:24239699, PubMed:27921136). The first step of the pathway is catalyzed by the aristolochene synthase which performs the cyclization of trans,trans-farnesyl diphosphate (FPP) to the bicyclic sesquiterpene aristolochene (PubMed:8440737, PubMed:15186158, PubMed:24239699). Following the formation of aristolochene, the non-oxygenated aristolochene is converted to the trioxygenated intermediate eremofortin B, via 7-epi-neopetasone (PubMed:24239699, PubMed:26274339). This conversion appears to involve three enzymes, a hydroxysterol oxidase-like enzyme, the quinone-oxidase prx3 that forms the quinone-type-structure in the bicyclic nucleus of aristolochene with the C8-oxo group and the C-3 hydroxyl group, and the P450 monooxygenase ORF6 that introduces the epoxide at the double bond between carbons 1 and 2 (PubMed:24239699, PubMed:27921136). No monoxy or dioxy-intermediates have been reported to be released to the broth, so these three early oxidative reactions may be coupled together (PubMed:24239699). Eremofortin B is further oxidized by another P450 monooxygenase, that introduces a second epoxide between carbons 7 and 11 prior to acetylation to eremofortin A by the acetyltransferase ORF8 (PubMed:16345540, PubMed:24239699, PubMed:27921136). The second epoxidation may be performed by a second P450 monooxygenase (PubMed:24239699). After the acetylation step, the conversion of eremofortin A to eremofortin C and then to PR-toxin requires only two enzymes (PubMed:24239699). First the conversion of eremofortin A to eremofortin C proceeds by oxidation of the side chain of the molecule at C-12 and is catalyzed by the short-chain oxidoreductase prx1 (PubMed:16345540, PubMed:24239699). The cytochrome P450 monooxygenase ORF5 plays also a role in this step (PubMed:27921136). The primary alcohol formed at C-12 is finally oxidized by the short-chain alcohol dehydrogenase prx4 that forms PR-toxin (PubMed:16345540, PubMed:24239699). {ECO:0000269|PubMed:15186158, ECO:0000269|PubMed:16345540, ECO:0000269|PubMed:24239699, ECO:0000269|PubMed:26274339, ECO:0000269|PubMed:27921136, ECO:0000269|PubMed:8440737}.

Catalytic activity: Reaction=(2E,6E)-farnesyl diphosphate = (+)-aristolochene + diphosphate; Xref=Rhea:RHEA:19825, ChEBI:CHEBI:33019, ChEBI:CHEBI:43445, ChEBI:CHEBI:175763; EC=4.2.3.9; Evidence={ECO:0000269|PubMed:15186158, ECO:0000269|PubMed:8440737};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250|UniProtKB:Q9UR08}; Note=Binds 3 Mg(2+) ions per subunit. {ECO:0000250|UniProtKB:Q9UR08};

Biophysicochemical properties: Kinetic parameters: KM=0.6 uM for (2E,6E)-farnesyl diphosphate {ECO:0000269|PubMed:15186158};

Pathway: Sesquiterpene biosynthesis; aristolochene biosynthesis; aristolochene from farnesyl diphosphate: step 1/1. {ECO:0000269|PubMed:15186158, ECO:0000269|PubMed:8440737}.

Subunit: Homodimer. {ECO:0000250|UniProtKB:Q9UR08}.

Disruption phenotype: Reduces the production of PR-toxin and leads to a large increase in mycophenolic acid production (PubMed:24239699). {ECO:0000269|PubMed:24239699}.

Similarity: Belongs to the terpene synthase family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Penicillium roqueforti.
Taxonomy:		Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes; Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.



Function:		Aristolochene synthase; part of the gene cluster that mediates the biosynthesis of PR-toxin, a bicyclic sesquiterpene belonging to the eremophilane class and acting as a mycotoxin (PubMed:24239699, PubMed:27921136). The first step of the pathway is catalyzed by the aristolochene synthase which performs the cyclization of trans,trans-farnesyl diphosphate (FPP) to the bicyclic sesquiterpene aristolochene (PubMed:8440737, PubMed:15186158, PubMed:24239699). Following the formation of aristolochene, the non-oxygenated aristolochene is converted to the trioxygenated intermediate eremofortin B, via 7-epi-neopetasone (PubMed:24239699, PubMed:26274339). This conversion appears to involve three enzymes, a hydroxysterol oxidase-like enzyme, the quinone-oxidase prx3 that forms the quinone-type-structure in the bicyclic nucleus of aristolochene with the C8-oxo group and the C-3 hydroxyl group, and the P450 monooxygenase ORF6 that introduces the epoxide at the double bond between carbons 1 and 2 (PubMed:24239699, PubMed:27921136). No monoxy or dioxy-intermediates have been reported to be released to the broth, so these three early oxidative reactions may be coupled together (PubMed:24239699). Eremofortin B is further oxidized by another P450 monooxygenase, that introduces a second epoxide between carbons 7 and 11 prior to acetylation to eremofortin A by the acetyltransferase ORF8 (PubMed:16345540, PubMed:24239699, PubMed:27921136). The second epoxidation may be performed by a second P450 monooxygenase (PubMed:24239699). After the acetylation step, the conversion of eremofortin A to eremofortin C and then to PR-toxin requires only two enzymes (PubMed:24239699). First the conversion of eremofortin A to eremofortin C proceeds by oxidation of the side chain of the molecule at C-12 and is catalyzed by the short-chain oxidoreductase prx1 (PubMed:16345540, PubMed:24239699). The cytochrome P450 monooxygenase ORF5 plays also a role in this step (PubMed:27921136). The primary alcohol formed at C-12 is finally oxidized by the short-chain alcohol dehydrogenase prx4 that forms PR-toxin (PubMed:16345540, PubMed:24239699). {ECO:0000269\|PubMed:15186158, ECO:0000269\|PubMed:16345540, ECO:0000269\|PubMed:24239699, ECO:0000269\|PubMed:26274339, ECO:0000269\|PubMed:27921136, ECO:0000269\|PubMed:8440737}.


Catalytic activity:		Reaction=(2E,6E)-farnesyl diphosphate = (+)-aristolochene + diphosphate; Xref=Rhea:RHEA:19825, ChEBI:CHEBI:33019, ChEBI:CHEBI:43445, ChEBI:CHEBI:175763; EC=4.2.3.9; Evidence={ECO:0000269\|PubMed:15186158, ECO:0000269\|PubMed:8440737};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250\|UniProtKB:Q9UR08}; Note=Binds 3 Mg(2+) ions per subunit. {ECO:0000250\|UniProtKB:Q9UR08};
Biophysicochemical properties:		Kinetic parameters: KM=0.6 uM for (2E,6E)-farnesyl diphosphate {ECO:0000269\|PubMed:15186158};
Pathway:		Sesquiterpene biosynthesis; aristolochene biosynthesis; aristolochene from farnesyl diphosphate: step 1/1. {ECO:0000269\|PubMed:15186158, ECO:0000269\|PubMed:8440737}.
Subunit:		Homodimer. {ECO:0000250\|UniProtKB:Q9UR08}.
Disruption phenotype:		Reduces the production of PR-toxin and leads to a large increase in mycophenolic acid production (PubMed:24239699). {ECO:0000269\|PubMed:24239699}.
Similarity:		Belongs to the terpene synthase family. {ECO:0000305}.