HMDH2_ASPFU
ID HMDH2_ASPFU Reviewed; 1062 AA.
AC Q4WSY2;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase 2 {ECO:0000303|PubMed:16110826};
DE Short=HMG-CoA reductase 2 {ECO:0000303|PubMed:16110826};
DE EC=1.1.1.34 {ECO:0000305|PubMed:16110826};
DE AltName: Full=Ergosterol biosynthesis protein hmg2 {ECO:0000303|PubMed:16110826};
GN Name=hmg2 {ECO:0000303|PubMed:16110826}; ORFNames=AFUA_1G11230;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP IDENTIFICATION, AND FUNCTION.
RX PubMed=16110826; DOI=10.1080/13693780400029114;
RA Ferreira M.E., Colombo A.L., Paulsen I., Ren Q., Wortman J., Huang J.,
RA Goldman M.H., Goldman G.H.;
RT "The ergosterol biosynthesis pathway, transporter genes, and azole
RT resistance in Aspergillus fumigatus.";
RL Med. Mycol. 43:S313-S319(2005).
RN [3]
RP FUNCTION.
RX PubMed=22106303; DOI=10.1073/pnas.1106399108;
RA Yasmin S., Alcazar-Fuoli L., Gruendlinger M., Puempel T., Cairns T.,
RA Blatzer M., Lopez J.F., Grimalt J.O., Bignell E., Haas H.;
RT "Mevalonate governs interdependency of ergosterol and siderophore
RT biosyntheses in the fungal pathogen Aspergillus fumigatus.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:E497-E504(2012).
CC -!- FUNCTION: HMG-CoA reductase; part of the first module of ergosterol
CC biosynthesis pathway that includes the early steps of the pathway,
CC conserved across all eukaryotes, and which results in the formation of
CC mevalonate from acetyl-coenzyme A (acetyl-CoA) (By similarity). Hmg1
CC and hmg2 catalyze the reduction of hydroxymethylglutaryl-CoA (HMG-CoA)
CC to mevalonate (By similarity). The first module starts with the action
CC of the cytosolic acetyl-CoA acetyltransferase erg10B that catalyzes the
CC formation of acetoacetyl-CoA. The hydroxymethylglutaryl-CoA synthases
CC erg13A and erg13B then condense acetyl-CoA with acetoacetyl-CoA to form
CC HMG-CoA. The rate-limiting step of the early module is the reduction to
CC mevalonate by the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
CC reductases hmg1 and hmg2. Mevalonate is also a precursor for the
CC extracellular siderophore triacetylfusarinine C (TAFC)
CC (PubMed:16110826, PubMed:22106303) (Probable).
CC {ECO:0000250|UniProtKB:Q4WHZ1, ECO:0000305|PubMed:16110826,
CC ECO:0000305|PubMed:22106303}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3-
CC methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10003,
CC ECO:0000305|PubMed:16110826};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000305|PubMed:16110826};
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC {ECO:0000305|PubMed:16110826}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; AAHF01000004; EAL90450.1; -; Genomic_DNA.
DR RefSeq; XP_752488.1; XM_747395.1.
DR SMR; Q4WSY2; -.
DR STRING; 746128.CADAFUBP00001046; -.
DR EnsemblFungi; EAL90450; EAL90450; AFUA_1G11230.
DR GeneID; 3510314; -.
DR KEGG; afm:AFUA_1G11230; -.
DR eggNOG; KOG2480; Eukaryota.
DR HOGENOM; CLU_001734_0_0_1; -.
DR InParanoid; Q4WSY2; -.
DR OMA; CVKLEIT; -.
DR OrthoDB; 907394at2759; -.
DR UniPathway; UPA00058; UER00103.
DR Proteomes; UP000002530; Chromosome 1.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005778; C:peroxisomal membrane; IBA:GO_Central.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IBA:GO_Central.
DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IBA:GO_Central.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR Gene3D; 1.10.3270.10; -; 1.
DR Gene3D; 3.30.70.420; -; 1.
DR Gene3D; 3.90.770.10; -; 1.
DR InterPro; IPR025583; HMG-CoA_N_dom.
DR InterPro; IPR002202; HMG_CoA_Rdtase.
DR InterPro; IPR023074; HMG_CoA_Rdtase_cat_sf.
DR InterPro; IPR023076; HMG_CoA_Rdtase_CS.
DR InterPro; IPR004554; HMG_CoA_Rdtase_eu_arc.
DR InterPro; IPR023282; HMG_CoA_Rdtase_N.
DR InterPro; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf.
DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf.
DR InterPro; IPR000731; SSD.
DR PANTHER; PTHR10572; PTHR10572; 1.
DR Pfam; PF00368; HMG-CoA_red; 1.
DR Pfam; PF13323; HPIH; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR PRINTS; PR00071; HMGCOARDTASE.
DR SUPFAM; SSF55035; SSF55035; 1.
DR SUPFAM; SSF56542; SSF56542; 1.
DR TIGRFAMs; TIGR00533; HMG_CoA_R_NADP; 1.
DR PROSITE; PS00066; HMG_COA_REDUCTASE_1; 1.
DR PROSITE; PS00318; HMG_COA_REDUCTASE_2; 1.
DR PROSITE; PS50065; HMG_COA_REDUCTASE_4; 1.
DR PROSITE; PS50156; SSD; 1.
PE 3: Inferred from homology;
KW Endoplasmic reticulum; Glycoprotein; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NADP; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..1062
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase 2"
FT /id="PRO_0000454151"
FT TOPO_DOM 1..34
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 35..55
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 56..230
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 231..251
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 252..261
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 262..282
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 283..287
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 288..308
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 309..355
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 356..375
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 376..377
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 378..398
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 399..450
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 451..471
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 472..564
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 565..585
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 586..1062
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DOMAIN 233..403
FT /note="SSD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199"
FT ACT_SITE 744
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 877
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 953
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 1049
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT BINDING 750..756
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 811..813
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 838..846
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 906..908
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 1048..1049
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 1053..1054
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT CARBOHYD 61
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 484
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1062 AA; 115278 MW; B4E08DEBB2C18AD5 CRC64;
MAPTNTKDSD TPGWLHRHGT SVLGSVARQA CKQPIYTLVI TALLATMTYT SLLEGSLYNA
NLTRLSNSHL NQLDVTDFLQ GSRSLRLGKA TAWQWETDDE SMSDQEVRPS FFLDPVASHL
ALITLVFPTS ENNPGISAVQ ESIISDLAAA QLVSRTPSVL SSTFRETSIT LSVPYNNLEE
VLRKTQNFPQ PEAEHSWTLK NAGKCNSGPK LRLWLIDVLA SFVGLIKHAQ IIDIIIMLLA
YLAMHLTFLS LFMSMRQLGS RFWLAYSVLL SGFFSLFFGL KVTTSSGVST SMITLSECLP
ILVIIVGFEK PIRLTRAVLR AATESYLPAK PMARRSTPEA IEVAIMREGW RIVRDYAIEI
AILAAGATSR VQGALPQFCF LAAWILLFDS LLLFTFYISV LCVKLEITRI RKHVEPRRAL
EDDDISTGNQ DFDSRVFGCK VKAANISRFK FLMVGGFVLF NVLQLSSLTY GNVRVSDWMP
YLSNLSNTLM PAPINPYRVA RNGLDDIYVA SRANNIETRV TVLPPIKYVL QSQSRHCRDN
FAGPLCDTLR GRTLGCVLAW LEDPVISKWV IAALFLSLVL NSYLMKAARW NLRQSEVIPD
SSATVSQTKD SSNKLAEKRT VDAMLQEGRV SLLEDEEIVN LCLRGKISAH ALEKTMERHP
TMSRLEAFTR AVKIRRTVVS RTPSTIDVSS SLEYSKAPFE NYDYTLVHGA CCENIIGYLP
LPVGAAGPLV IDGRNYFIPM ATTEGVLVAS ASRGCKAINA GGGAVTVINA DGMTRGPCLA
FSSVSRAAEA KQWIDSDEGK KILATAFNST SRFARLQGLK SAQAGTYLYV RFKSTTGDAM
GMNMISKGVE KALEVMKGHG FSDMSTISVT GNYCVDKKPA AINWIDGRGK SVVAEALIPA
DAVRSVLKTD VDALVELNTA KNLVGSAMAG SIGGFNVHAS NLVAAVLLAT GQDPAQNVES
SSCITIMKNV NNNLHISVSM PCIEVGTIGG GTILEPQAAM LDLLGVRGAH ATNPGDNARQ
LARIVAAAVL AGELSTCAAL AAGHLVSAHM AHNRSKVAAK TG
