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 02-DEC-2020, entry version 6. 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). 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 lead compound for the treatment of hyper-cholesterolemia by targeting CC squalene synthase (SS) (PubMed:27056201). Both phenylalanine and CC benzoic acid are known precursors of SQS1 and so it is unsurprising CC that the cluster also contains genes potentially involved in benzoate CC production such as phenyl-alanine ammonia lysase (PAL) M7, which CC catalyzes the first step in the degradation of phenylalanine, or the CC NADP-dependent dehydrogenase M3 (PubMed:27056201). The cluster contains CC two PKS encoding genes. The tetraketide synthase is responsible for the CC biosynthesis of the tetraketide sidechain of SQS1 (By similarity). The CC biosynthesis must involve 3 rounds of chain extension. After the first CC and second rounds methyl-transfer occurs, and in all rounds of CC extension the ketoreductase and dehydratase areactive. The enoyl CC reductase and C-MeT are not active in the final round of extension (By CC similarity). The other PKS is therefore likely to encode squalestatin CC hexaketide synthase (SQHKS) (PubMed:27056201). The hexaketide main CC chain is initiated by benzoate which is an unusual starter unit for a CC highly reducing polyketide synthase (PubMed:27056201). The cluster also CC contains a gene encoding a citrate synthase-like protein R3 presumably CC involved in linking the hexaketide to the oxaloacetate moiety CC (Probable). Formation of the tetraketide CoA may be catalyzed by the M9 CC CoA ligase, but the mechanism of release of the tetraketide and the CC hexaketide from their respective PKS remains unknown, although the CC cluster encodes a potential esterase (M8) and a possible hydrolase CC (M10) which could be involved in these processes (Probable). Two CC acyltransferases (AT), M4 and R4, are also encoded in the cluster. M4 CC is responsible for loading of the tetraketide sidechain from CoA onto CC the squalestatin core as the final step of biosynthesis CC (PubMed:27056201). M4 appears to have a broad substrate selectivity for CC its acyl CoA substrate, allowing the in vitro synthesis of novel CC squalestatins (PubMed:27056201). The biosynthesis of SQS1 requires CC several oxidative steps likely performed by oxidoreductases M1, R1 and CC R2 (Probable). Finally, in support of the identification of the cluster CC as 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 (PubMed:27056201). CC {ECO:0000250|UniProtKB:Q86ZD9, ECO:0000269|PubMed:27056201, CC 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 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 //