ID   HMDH_HALVD              Reviewed;         403 AA.
AC   Q59468; D4GU18;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   21-SEP-2011, sequence version 2.
DT   03-AUG-2022, entry version 123.
DE   RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase;
DE            Short=HMG-CoA reductase;
DE            Short=HMGR;
DE            EC=1.1.1.34;
GN   Name=hmgA; Synonyms=hmg, hmgR; OrderedLocusNames=HVO_2583;
OS   Haloferax volcanii (strain ATCC 29605 / DSM 3757 / JCM 8879 / NBRC 14742 /
OS   NCIMB 2012 / VKM B-1768 / DS2) (Halobacterium volcanii).
OC   Archaea; Euryarchaeota; Stenosarchaea group; Halobacteria; Haloferacales;
OC   Haloferacaceae; Haloferax.
OX   NCBI_TaxID=309800;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=DS2 / DSM 5716 / WFD11;
RX   PubMed=1556098; DOI=10.1016/s0021-9258(18)42628-2;
RA   Lam W.L., Doolittle W.F.;
RT   "Mevinolin-resistant mutations identify a promoter and the gene for a
RT   eukaryote-like 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the
RT   archaebacterium Haloferax volcanii.";
RL   J. Biol. Chem. 267:5829-5834(1992).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 29605 / DSM 3757 / JCM 8879 / NBRC 14742 / NCIMB 2012 / VKM
RC   B-1768 / DS2;
RX   PubMed=20333302; DOI=10.1371/journal.pone.0009605;
RA   Hartman A.L., Norais C., Badger J.H., Delmas S., Haldenby S., Madupu R.,
RA   Robinson J., Khouri H., Ren Q., Lowe T.M., Maupin-Furlow J.,
RA   Pohlschroder M., Daniels C., Pfeiffer F., Allers T., Eisen J.A.;
RT   "The complete genome sequence of Haloferax volcanii DS2, a model
RT   archaeon.";
RL   PLoS ONE 5:E9605-E9605(2010).
RN   [3]
RP   PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, INDUCTION, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY.
RC   STRAIN=DS2 / DSM 5716 / WFD11;
RX   PubMed=16969709; DOI=10.1007/s00792-006-0008-3;
RA   Bidle K.A., Hanson T.E., Howell K., Nannen J.;
RT   "HMG-CoA reductase is regulated by salinity at the level of transcription
RT   in Haloferax volcanii.";
RL   Extremophiles 11:49-55(2007).
RN   [4]
RP   FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP   REGULATION, AND PATHWAY.
RC   STRAIN=DS2 / DSM 5716 / WFD11;
RX   PubMed=8550415; DOI=10.1128/jb.178.1.19-23.1996;
RA   Bischoff K.M., Rodwell V.W.;
RT   "3-Hydroxy-3-methylglutaryl-coenzyme A reductase from Haloferax volcanii:
RT   purification, characterization, and expression in Escherichia coli.";
RL   J. Bacteriol. 178:19-23(1996).
CC   -!- FUNCTION: Catalyzes the NADPH-dependent reductive deacylation of (S)-3-
CC       hydroxy-3-methylglutaryl-CoA (HMG-CoA) to (R)-mevalonate. Functions in
CC       the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP),
CC       a key precursor for the biosynthesis of isoprenoid compounds such as
CC       archaeal membrane lipids. Is also able to catalyze the reduction of
CC       mevaldehyde to mevalonate and the oxidative acylation of mevaldehyde to
CC       HMG-CoA. {ECO:0000269|PubMed:16969709, ECO:0000269|PubMed:8550415}.
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:0000269|PubMed:8550415};
CC   -!- ACTIVITY REGULATION: Is competitively inhibited by (R)-HMG-CoA and
CC       lovastatin (formerly called mevinolin). {ECO:0000269|PubMed:8550415}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=46 uM for (S)-HMG-CoA {ECO:0000269|PubMed:8550415};
CC         KM=66 uM for NADPH {ECO:0000269|PubMed:8550415};
CC         Vmax=34 umol/min/mg enzyme for the reductive deacylation of HMG-CoA
CC         {ECO:0000269|PubMed:8550415};
CC       pH dependence:
CC         Optimum pH is 7.3 for the reductive deacylation of HMG-CoA (in the
CC         presence of 3 M KCl). {ECO:0000269|PubMed:8550415};
CC   -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC       biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC       {ECO:0000269|PubMed:8550415}.
CC   -!- INDUCTION: Up-regulated during growth at high salinity.
CC       {ECO:0000269|PubMed:16969709}.
CC   -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR   EMBL; M83531; AAA73174.1; -; Genomic_DNA.
DR   EMBL; CP001956; ADE02906.1; -; Genomic_DNA.
DR   PIR; A42149; A42149.
DR   RefSeq; WP_004042652.1; NZ_AOHU01000046.1.
DR   AlphaFoldDB; Q59468; -.
DR   SMR; Q59468; -.
DR   STRING; 309800.C498_08195; -.
DR   EnsemblBacteria; ADE02906; ADE02906; HVO_2583.
DR   GeneID; 8926248; -.
DR   KEGG; hvo:HVO_2583; -.
DR   eggNOG; arCOG04260; Archaea.
DR   HOGENOM; CLU_001734_2_2_2; -.
DR   OMA; DDKMTRA; -.
DR   OrthoDB; 26445at2157; -.
DR   BioCyc; MetaCyc:MON-21127; -.
DR   BRENDA; 1.1.1.34; 2561.
DR   UniPathway; UPA00058; UER00103.
DR   Proteomes; UP000008243; Chromosome.
DR   GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IEA:UniProtKB-EC.
DR   GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR   GO; GO:0008299; P:isoprenoid biosynthetic process; IEA:UniProtKB-KW.
DR   CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR   Gene3D; 3.30.70.420; -; 1.
DR   Gene3D; 3.90.770.10; -; 1.
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; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf.
DR   InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf.
DR   PANTHER; PTHR10572; PTHR10572; 1.
DR   Pfam; PF00368; HMG-CoA_red; 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.
PE   1: Evidence at protein level;
KW   Direct protein sequencing; Isoprene biosynthesis; Lipid biosynthesis;
KW   Lipid metabolism; NADP; Oxidoreductase; Reference proteome.
FT   CHAIN           1..403
FT                   /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase"
FT                   /id="PRO_0000114460"
FT   ACT_SITE        99
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        303
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        398
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250"
FT   CONFLICT        264..266
FT                   /note="AVA -> RGR (in Ref. 1; AAA73174)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   403 AA;  41085 MW;  A85C7F7FE7E94833 CRC64;
     MTDAASLADR VREGDLRLHE LEAHADADTA AEARRLLVES QSGASLDAVG NYGFPAEAAE
     SAIENMVGSI QVPMGVAGPV SVDGGSVAGE KYLPLATTEG ALLASVNRGC SVINSAGGAT
     ARVLKSGMTR APVFRVADVA EAEALVSWTR DNFAALKEAA EETTNHGELL DVTPYVVGNS
     VYLRFRYDTK DAMGMNMATI ATEAVCGVVE AETAASLVAL SGNLCSDKKP AAINAVEGRG
     RSVTADVRIP REVVEERLHT TPEAVAELNT RKNLVGSAKA ASLGFNAHVA NVVAAMFLAT
     GQDEAQVVEG ANAITTAEVQ DGDLYVSVSI ASLEVGTVGG GTKLPTQSEG LDILGVSGGG
     DPAGSNADAL AECIAVGSLA GELSLLSALA SRHLSSAHAE LGR