ID MFR2_PHOSM Reviewed; 293 AA. AC A0A3G1DJF4; DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot. DT 13-FEB-2019, sequence version 1. DT 25-MAY-2022, entry version 9. DE RecName: Full=Oxidoreductase R2 {ECO:0000303|PubMed:27056201}; DE EC=1.-.-.- {ECO:0000305|PubMed:27056201}; DE AltName: Full=Squalestatin S1 biosynthesis cluster protein R2 {ECO:0000303|PubMed:27056201}; GN Name=R2 {ECO:0000303|PubMed:27056201}; OS Phoma sp. (strain ATCC 20986 / MF5453). OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes; OC Pleosporomycetidae; Pleosporales; Pleosporineae; Didymellaceae; Phoma. OX NCBI_TaxID=1828523; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION. RX PubMed=27056201; DOI=10.1039/c6cc02130a; RA Bonsch B., Belt V., Bartel C., Duensing N., Koziol M., Lazarus C.M., RA Bailey A.M., Simpson T.J., Cox R.J.; RT "Identification of genes encoding squalestatin S1 biosynthesis and in vitro RT production of new squalestatin analogues."; RL Chem. Commun. (Camb.) 52:6777-6780(2016). RN [2] RP FUNCTION. RX PubMed=11251290; DOI=10.1016/s1074-5521(00)90064-4; RA Nicholson T.P., Rudd B.A., Dawson M., Lazarus C.M., Simpson T.J., Cox R.J.; RT "Design and utility of oligonucleotide gene probes for fungal polyketide RT synthases."; RL Chem. Biol. 8:157-178(2001). RN [3] RP FUNCTION. RX PubMed=15489970; DOI=10.1039/b411973h; RA Cox R.J., Glod F., Hurley D., Lazarus C.M., Nicholson T.P., Rudd B.A., RA Simpson T.J., Wilkinson B., Zhang Y.; RT "Rapid cloning and expression of a fungal polyketide synthase gene involved RT in squalestatin biosynthesis."; RL Chem. Commun. (Camb.) 2004:2260-2261(2004). RN [4] RP FUNCTION. RX PubMed=28106181; DOI=10.1039/c6cc10172k; RA Liddle E., Scott A., Han L.C., Ivison D., Simpson T.J., Willis C.L., RA Cox R.J.; RT "In vitro kinetic study of the squalestatin tetraketide synthase RT dehydratase reveals the stereochemical course of a fungal highly reducing RT polyketide synthase."; RL Chem. Commun. (Camb.) 53:1727-1730(2017). CC -!- FUNCTION: Oxidoreductase; part of the gene cluster that mediates the CC biosynthesis of squalestatin S1 (SQS1, also known as zaragozic acid A), CC a heavily oxidized fungal polyketide that offers potent cholesterol CC lowering activity by targeting squalene synthase (SS) CC (PubMed:27056201). SQS1 is composed of a 2,8- CC dioxobicyclic[3.2.1]octane-3,4,5-tricarboxyclic acid core that is CC connected to two lipophilic polyketide arms (PubMed:27056201). These CC initial steps feature the priming of an unusual benzoic acid starter CC unit onto the highly reducing polyketide synthase pks2, followed by CC oxaloacetate extension and product release to generate a tricarboxylic CC acid containing product (By similarity). The phenylalanine ammonia CC lyase (PAL) M7 and the acyl-CoA ligase M9 are involved in transforming CC phenylalanine into benzoyl-CoA (By similarity). The citrate synthase- CC like protein R3 is involved in connecting the C-alpha-carbons of the CC hexaketide chain and oxaloacetate to afford the tricarboxylic acid unit CC (By similarity). The potential hydrolytic enzymes, M8 and M10, are in CC close proximity to pks2 and may participate in product release (By CC similarity). On the other side, the tetraketide arm is synthesized by a CC the squalestatin tetraketide synthase pks1 and enzymatically esterified CC to the core in the last biosynthetic step, by the acetyltransferase M4 CC (PubMed:11251290, PubMed:15489970, PubMed:28106181). The biosynthesis CC of the tetraketide must involve 3 rounds of chain extension CC (PubMed:11251290, PubMed:15489970, PubMed:28106181). After the first CC and second rounds methyl-transfer occurs, and in all rounds of CC extension the ketoreductase and dehydratase are active CC (PubMed:11251290, PubMed:15489970, PubMed:28106181). The enoyl CC reductase and C-MeT of pks1 are not active in the final round of CC extension (PubMed:11251290, PubMed:15489970, PubMed:28106181). The CC acetyltransferase M4 appears to have a broad substrate selectivity for CC its acyl CoA substrate, allowing the in vitro synthesis of novel CC squalestatins (Probable). The biosynthesis of SQS1 requires several CC oxidative steps likely performed by oxidoreductases M1, R1 and R2 CC (Probable). Finally, in support of the identification of the cluster as CC being responsible for SQS1 production, the cluster contains a gene CC encoding a putative squalene synthase (SS) R6, suggesting a likely CC mechanism for self-resistance (Probable). CC {ECO:0000250|UniProtKB:A0A345BJP7, ECO:0000269|PubMed:11251290, CC ECO:0000269|PubMed:15489970, ECO:0000269|PubMed:27056201, CC ECO:0000269|PubMed:28106181, ECO:0000305|PubMed:27056201}. CC -!- PATHWAY: Secondary metabolite biosynthesis. CC {ECO:0000305|PubMed:27056201}. CC -!- SIMILARITY: Belongs to the asaB hydroxylase/desaturase family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; KU946987; AMY15070.1; -; Genomic_DNA. DR AlphaFoldDB; A0A3G1DJF4; -. DR SMR; A0A3G1DJF4; -. DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW. DR InterPro; IPR044053; AsaB-like. DR PANTHER; PTHR34598; PTHR34598; 1. PE 3: Inferred from homology; KW Oxidoreductase. FT CHAIN 1..293 FT /note="Oxidoreductase R2" FT /id="PRO_0000447840" SQ SEQUENCE 293 AA; 33777 MW; 098A01059F50319F CRC64; MATATTTLHS TTGTVYVADG TTDGKVGYYN HTDDSTNVIR KPIPIEVEDA RTLSKSPTTK AEGYQLVNFH TKIPEEHFLN SKLPENKELI EEVYFDECRR LVQEVTGAAE AYPYVYRVRN QEQNAKESNK SNFHTDFVPI VHVDRDDVTA PQRLRASLGA EKADMLLSKY KSYGSINVWR PVKNMVQKWP LMLVDHKSIE DWDYSTHMFT LHSSNDERVA TRGAKEHETI LTHDKRYRYI YASDMTPEEA WLFFAFHSDP ALGIPHGAFW DDSTKEEALT RCSIEVRIWV FFD //