HMGCS_ENTFL
ID HMGCS_ENTFL Reviewed; 383 AA.
AC Q9FD71;
DT 11-JUN-2014, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 95.
DE RecName: Full=Hydroxymethylglutaryl-CoA synthase;
DE Short=HMG-CoA synthase;
DE Short=HMGCS;
DE EC=2.3.3.10;
DE AltName: Full=3-hydroxy-3-methylglutaryl coenzyme A synthase;
GN Name=mvaS;
OS Enterococcus faecalis (Streptococcus faecalis).
OC Bacteria; Firmicutes; Bacilli; Lactobacillales; Enterococcaceae;
OC Enterococcus.
OX NCBI_TaxID=1351;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND PATHWAY.
RX PubMed=10894743; DOI=10.1128/jb.182.15.4319-4327.2000;
RA Wilding E.I., Brown J.R., Bryant A.P., Chalker A.F., Holmes D.J.,
RA Ingraham K.A., Iordanescu S., So C.Y., Rosenberg M., Gwynn M.N.;
RT "Identification, evolution, and essentiality of the mevalonate pathway for
RT isopentenyl diphosphate biosynthesis in gram-positive cocci.";
RL J. Bacteriol. 182:4319-4327(2000).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=12107122; DOI=10.1128/jb.184.15.4065-4070.2002;
RA Sutherlin A., Hedl M., Sanchez-Neri B., Burgner J.W. II, Stauffacher C.V.,
RA Rodwell V.W.;
RT "Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an
RT enzyme of isopentenyl diphosphate biosynthesis.";
RL J. Bacteriol. 184:4065-4070(2002).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, KINETIC PARAMETERS, AND ACTIVITY REGULATION.
RX PubMed=23794621; DOI=10.1128/jb.00485-13;
RA VanNice J.C., Skaff D.A., Wyckoff G.J., Miziorko H.M.;
RT "Expression in Haloferax volcanii of 3-hydroxy-3-methylglutaryl coenzyme A
RT synthase facilitates isolation and characterization of the active form of a
RT key enzyme required for polyisoprenoid cell membrane biosynthesis in
RT halophilic archaea.";
RL J. Bacteriol. 195:3854-3862(2013).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF APOENZYME AND OF A COVALENT
RP ACETOACETYL-ENZYME ADDUCT IN COMPLEX WITH COA, SUBUNIT, ACTIVITY
RP REGULATION, ACTIVE SITE, AND REACTION MECHANISM.
RX PubMed=16245942; DOI=10.1021/bi051487x;
RA Steussy C.N., Vartia A.A., Burgner J.W., Sutherlin A., Rodwell V.W.,
RA Stauffacher C.V.;
RT "X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis
RT and a complex with its second substrate/inhibitor acetoacetyl-CoA.";
RL Biochemistry 44:14256-14267(2005).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF MUTANT GLY-110, AND MUTAGENESIS
RP OF ALA-110.
RX PubMed=17128980; DOI=10.1021/bi061505q;
RA Steussy C.N., Robison A.D., Tetrick A.M., Knight J.T., Rodwell V.W.,
RA Stauffacher C.V., Sutherlin A.L.;
RT "A structural limitation on enzyme activity: the case of HMG-CoA
RT synthase.";
RL Biochemistry 45:14407-14414(2006).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF APOENZYME AND IN COMPLEX WITH
RP HYMEGLUSIN INHIBITOR VIA A COVALENT LINKAGE, AND ACTIVITY REGULATION.
RX PubMed=22510038; DOI=10.1021/bi300037k;
RA Skaff D.A., Ramyar K.X., McWhorter W.J., Barta M.L., Geisbrecht B.V.,
RA Miziorko H.M.;
RT "Biochemical and structural basis for inhibition of Enterococcus faecalis
RT hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin.";
RL Biochemistry 51:4713-4722(2012).
CC -!- FUNCTION: Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA
CC to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Functions in the
CC mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a
CC key precursor for the biosynthesis of isoprenoid compounds.
CC {ECO:0000269|PubMed:12107122, ECO:0000269|PubMed:23794621}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetoacetyl-CoA + acetyl-CoA + H2O = (3S)-hydroxy-3-
CC methylglutaryl-CoA + CoA + H(+); Xref=Rhea:RHEA:10188,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57286, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288; EC=2.3.3.10;
CC Evidence={ECO:0000269|PubMed:12107122, ECO:0000269|PubMed:23794621};
CC -!- ACTIVITY REGULATION: Is sensitive to feedback substrate inhibition by
CC acetoacetyl-CoA. Is inactivated by hymeglusin, which also blocks the
CC growth of E.faecalis, indicating the critical role that the mevalonate
CC pathway plays in isoprenoid biosynthesis. {ECO:0000269|PubMed:16245942,
CC ECO:0000269|PubMed:22510038, ECO:0000269|PubMed:23794621}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=350 uM for acetyl-CoA {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:23794621};
CC KM=10 uM for acetoacetyl-CoA {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:23794621};
CC KM=400 uM for acetyl-CoA {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:23794621};
CC KM=0.5 uM for acetoacetyl-CoA {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:23794621};
CC Vmax=10 umol/min/mg enzyme {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:23794621};
CC Vmax=5.3 umol/min/mg enzyme {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:23794621};
CC pH dependence:
CC Optimum pH is about 9.8. {ECO:0000269|PubMed:12107122};
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius.
CC {ECO:0000269|PubMed:12107122};
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 2/3.
CC {ECO:0000269|PubMed:10894743}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:12107122,
CC ECO:0000269|PubMed:16245942, ECO:0000269|PubMed:22510038}.
CC -!- SIMILARITY: Belongs to the thiolase-like superfamily. HMG-CoA synthase
CC family. {ECO:0000305}.
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DR EMBL; AF290092; AAG02438.1; -; Genomic_DNA.
DR RefSeq; WP_002357756.1; NZ_WYAE01000001.1.
DR PDB; 1X9E; X-ray; 2.40 A; A/B=1-383.
DR PDB; 1YSL; X-ray; 1.90 A; A/B=1-383.
DR PDB; 2HDB; X-ray; 2.20 A; A/B=1-383.
DR PDB; 3V4N; X-ray; 1.60 A; A/B/C/D=1-383.
DR PDB; 3V4X; X-ray; 1.95 A; A/B/C/D=1-383.
DR PDBsum; 1X9E; -.
DR PDBsum; 1YSL; -.
DR PDBsum; 2HDB; -.
DR PDBsum; 3V4N; -.
DR PDBsum; 3V4X; -.
DR AlphaFoldDB; Q9FD71; -.
DR SMR; Q9FD71; -.
DR STRING; 1201292.DR75_437; -.
DR GeneID; 60893745; -.
DR eggNOG; COG3425; Bacteria.
DR OrthoDB; 872193at2; -.
DR BioCyc; MetaCyc:MON-18245; -.
DR BRENDA; 2.3.3.10; 2095.
DR SABIO-RK; Q9FD71; -.
DR UniPathway; UPA00058; UER00102.
DR EvolutionaryTrace; Q9FD71; -.
DR GO; GO:0004421; F:hydroxymethylglutaryl-CoA synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0006084; P:acetyl-CoA metabolic process; IEA:InterPro.
DR GO; GO:0010142; P:farnesyl diphosphate biosynthetic process, mevalonate pathway; IEA:InterPro.
DR Gene3D; 3.40.47.10; -; 2.
DR InterPro; IPR013746; HMG_CoA_synt_C_dom.
DR InterPro; IPR013528; HMG_CoA_synth_N.
DR InterPro; IPR011554; HMG_CoA_synthase_prok.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF08540; HMG_CoA_synt_C; 2.
DR Pfam; PF01154; HMG_CoA_synt_N; 1.
DR SUPFAM; SSF53901; SSF53901; 2.
DR TIGRFAMs; TIGR01835; HMG-CoA-S_prok; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acyltransferase; Isoprene biosynthesis; Transferase.
FT CHAIN 1..383
FT /note="Hydroxymethylglutaryl-CoA synthase"
FT /id="PRO_0000429271"
FT ACT_SITE 79
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT ACT_SITE 111
FT /note="Acyl-thioester intermediate"
FT /evidence="ECO:0000269|PubMed:16245942"
FT ACT_SITE 233
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 29
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 201
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 275
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT MUTAGEN 110
FT /note="A->G: 140-fold increase in the overall reaction
FT rate, and 86-fold increase in catalytic efficiency."
FT /evidence="ECO:0000269|PubMed:17128980"
FT STRAND 3..11
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 14..18
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 19..25
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 31..34
FT /evidence="ECO:0007829|PDB:3V4N"
FT TURN 35..37
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 41..43
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 51..60
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 65..70
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 71..77
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 82..86
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 88..95
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 103..109
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 110..112
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 113..127
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 132..141
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 150..152
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 154..165
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 167..171
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 176..179
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 184..186
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 198..220
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 224..226
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 228..232
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 237..247
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 253..266
FT /evidence="ECO:0007829|PDB:3V4N"
FT TURN 267..269
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 270..272
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 277..279
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 280..291
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 300..307
FT /evidence="ECO:0007829|PDB:3V4N"
FT TURN 308..310
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 311..319
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 323..325
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 329..337
FT /evidence="ECO:0007829|PDB:3V4N"
FT HELIX 344..352
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 371..375
FT /evidence="ECO:0007829|PDB:3V4N"
FT STRAND 378..381
FT /evidence="ECO:0007829|PDB:3V4N"
SQ SEQUENCE 383 AA; 42151 MW; C3BE0D765FF15E42 CRC64;
MTIGIDKISF FVPPYYIDMT ALAEARNVDP GKFHIGIGQD QMAVNPISQD IVTFAANAAE
AILTKEDKEA IDMVIVGTES SIDESKAAAV VLHRLMGIQP FARSFEIKEA CYGATAGLQL
AKNHVALHPD KKVLVVAADI AKYGLNSGGE PTQGAGAVAM LVASEPRILA LKEDNVMLTQ
DIYDFWRPTG HPYPMVDGPL SNETYIQSFA QVWDEHKKRT GLDFADYDAL AFHIPYTKMG
KKALLAKISD QTEAEQERIL ARYEESIIYS RRVGNLYTGS LYLGLISLLE NATTLTAGNQ
IGLFSYGSGA VAEFFTGELV AGYQNHLQKE THLALLDNRT ELSIAEYEAM FAETLDTDID
QTLEDELKYS ISAINNTVRS YRN
