ID   HTYA_ASPRU              Reviewed;         584 AA.
AC   K0E4E5;
DT   25-APR-2018, integrated into UniProtKB/Swiss-Prot.
DT   28-NOV-2012, sequence version 1.
DT   03-AUG-2022, entry version 21.
DE   RecName: Full=Isopropyl malate synthase htyA {ECO:0000303|PubMed:22998630};
DE            EC=2.3.3.13 {ECO:0000305|PubMed:22998630};
DE   AltName: Full=L-homotyrosine biosynthetic cluster protein A {ECO:0000303|PubMed:22998630};
GN   Name=htyA {ECO:0000303|PubMed:22998630};
OS   Aspergillus rugulosus (Emericella rugulosa).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX   NCBI_TaxID=41736;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, PATHWAY,
RP   AND BIOTECHNOLOGY.
RC   STRAIN=ATCC 58397 / NRRL 11440;
RX   PubMed=22998630; DOI=10.1021/ja307220z;
RA   Cacho R.A., Jiang W., Chooi Y.H., Walsh C.T., Tang Y.;
RT   "Identification and characterization of the echinocandin B biosynthetic
RT   gene cluster from Emericella rugulosa NRRL 11440.";
RL   J. Am. Chem. Soc. 134:16781-16790(2012).
RN   [2]
RP   FUNCTION.
RX   PubMed=29352089; DOI=10.1128/aem.02370-17;
RA   Mattay J., Houwaart S., Huettel W.;
RT   "Cryptic production of trans-3-hydroxyproline in echinocandin B
RT   biosynthesis.";
RL   Appl. Environ. Microbiol. 0:0-0(2018).
CC   -!- FUNCTION: Isopropyl malate synthase; part of the gene cluster that
CC       mediates the de novo generation of L-homotyrosine from acetyl-CoA and
CC       4-hydroxyphenyl-pyruvate (PubMed:22998630). L-homotyrosine is a
CC       building block of echinocandin B, a fungal lipidated cyclic hexapeptide
CC       that acts as an antifungal agent (PubMed:22998630). L-homotyrosine 4-
CC       hydroxyphenyl-pyruvate first undergoes an aldol-type condensation by
CC       htyA with the C-2 of acetyl-CoA followed by the release of CoA to form
CC       2-(4-hydroxybenzyl)-malate (PubMed:22998630). This is followed by
CC       isomerization of 2-(4-hydroxy-benzyl)-malate to 3-(4-hydroxybenzyl)-
CC       malate by htyD (PubMed:22998630). Thereafter, 3-(4-hydroxybenzyl)-
CC       malate undergoes decarboxylation and oxidation to form 2-oxo-4-(4-
CC       hydroxybenzyl)butanoic acid, coupled to reduction of NAD(+) to NADH by
CC       htyC (PubMed:22998630). The product then undergoes transamination
CC       catalyzed by htyB to form L-homotyrosine (PubMed:22998630).
CC       {ECO:0000269|PubMed:22998630}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3-methyl-2-oxobutanoate + acetyl-CoA + H2O = (2S)-2-
CC         isopropylmalate + CoA + H(+); Xref=Rhea:RHEA:21524, ChEBI:CHEBI:1178,
CC         ChEBI:CHEBI:11851, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57287, ChEBI:CHEBI:57288; EC=2.3.3.13;
CC         Evidence={ECO:0000305|PubMed:22998630};
CC   -!- PATHWAY: Antifungal biosynthesis. {ECO:0000269|PubMed:22998630}.
CC   -!- DISRUPTION PHENOTYPE: Impairs the production of echinocandin B and the
CC       ability to inhibit the growth of C.albicans under screening conditions
CC       (PubMed:22998630). {ECO:0000269|PubMed:22998630}.
CC   -!- BIOTECHNOLOGY: Due to their effectiveness as antifungal agents,
CC       echinocandin derivatives can be used for the treatment of human
CC       invasive candidiasis (PubMed:22998630). {ECO:0000269|PubMed:22998630}.
CC   -!- SIMILARITY: Belongs to the alpha-IPM synthase/homocitrate synthase
CC       family. LeuA type 2 subfamily. {ECO:0000305}.
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DR   EMBL; JX421685; AFT91393.1; -; Genomic_DNA.
DR   AlphaFoldDB; K0E4E5; -.
DR   SMR; K0E4E5; -.
DR   BioCyc; MetaCyc:MON-19234; -.
DR   GO; GO:0003852; F:2-isopropylmalate synthase activity; IEA:UniProtKB-EC.
DR   GO; GO:0019752; P:carboxylic acid metabolic process; IEA:InterPro.
DR   GO; GO:0044249; P:cellular biosynthetic process; IEA:UniProt.
DR   GO; GO:1901566; P:organonitrogen compound biosynthetic process; IEA:UniProt.
DR   GO; GO:0044238; P:primary metabolic process; IEA:UniProt.
DR   GO; GO:0044283; P:small molecule biosynthetic process; IEA:UniProt.
DR   Gene3D; 3.20.20.70; -; 1.
DR   Gene3D; 3.30.160.270; -; 1.
DR   InterPro; IPR002034; AIPM/Hcit_synth_CS.
DR   InterPro; IPR013785; Aldolase_TIM.
DR   InterPro; IPR036230; LeuA_allosteric_dom_sf.
DR   InterPro; IPR000891; PYR_CT.
DR   Pfam; PF00682; HMGL-like; 1.
DR   PROSITE; PS00815; AIPM_HOMOCIT_SYNTH_1; 1.
DR   PROSITE; PS00816; AIPM_HOMOCIT_SYNTH_2; 1.
DR   PROSITE; PS50991; PYR_CT; 1.
PE   1: Evidence at protein level;
KW   Transferase.
FT   CHAIN           1..584
FT                   /note="Isopropyl malate synthase htyA"
FT                   /id="PRO_0000443851"
FT   DOMAIN          39..317
FT                   /note="Pyruvate carboxyltransferase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01151"
SQ   SEQUENCE   584 AA;  63714 MW;  4409542AE6AF5A2A CRC64;
     MSTICAGGQT LESKYGGRAP PQIQLPDRQW PSKKLTESPI WLSTDLRDGN QALPNPMTTS
     QKWQMFRLLV DIGFKQIEVS FPCASDTEYT FTRALVETPG AVPDDVSLEV MTPCRKETLV
     RAVESLKGAK KAILFTYLAT SDNYRETILQ RSEAETLEHV RDCIEYARAI TKEDPEARQT
     EWSLGFGMED FANARPDAAL RLAEVIQAAW QPSRENPVIL GLASSVEAAT VNIFADQVEY
     FSRHLSSRET VCISIHTHND RGGAAAAAEL ACLAGGDRVE GCLFGNGERA GNLDLVTAAM
     NCFTQGMETG LDFSNLPEIR RVYESITQLP VHPRTPYSGD YYFRAFSGAH QDAIRKGLQK
     RAANSSKSPW KVPYLPLDPA DLGVSFDNVI GVNSQSGKGG VAWLIQNGLA LSIPTQLAAS
     FSHVVKEQSV AQERGLAAEE ICALFADRYD LRDSPSGRVV REHGYIAAFQ HPGCALELED
     VTEQAARAAG ILTRGLDFLL RCTRAASHPL GGPDDSNLTV AFVQCAVTEK AEEAWGIGIG
     FSQDSAIDRA LLSVMNRHYQ PTPIRAPLAT NDSVIPRPEP IRGG