ID   MDHC_PIG                Reviewed;         334 AA.
AC   P11708; Q29560;
DT   01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 4.
DT   24-JAN-2024, entry version 178.
DE   RecName: Full=Malate dehydrogenase, cytoplasmic;
DE            EC=1.1.1.37;
DE   AltName: Full=Aromatic alpha-keto acid reductase {ECO:0000305};
DE            Short=KAR {ECO:0000305};
DE            EC=1.1.1.96 {ECO:0000250|UniProtKB:P40925};
DE   AltName: Full=Cytosolic malate dehydrogenase;
GN   Name=MDH1;
OS   Sus scrofa (Pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX   NCBI_TaxID=9823;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RC   TISSUE=Heart;
RX   PubMed=8682322; DOI=10.1016/0378-1119(96)00178-3;
RA   Trejo F., Costa M., Gelpi J.L., Busquets M., Clarke A.R., Holbrook J.J.,
RA   Cortes A.;
RT   "Cloning, sequencing and functional expression of a DNA encoding pig
RT   cytosolic malate dehydrogenase: purification and characterization of the
RT   recombinant enzyme.";
RL   Gene 172:303-308(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 46-334.
RX   PubMed=3312200; DOI=10.1016/s0021-9258(18)48147-1;
RA   Joh T., Takeshima H., Tsuzuki T., Setoyama C., Shimada K., Tanase S.,
RA   Kuramitsu S., Kagamiyama H., Morino Y.;
RT   "Cloning and sequence analysis of cDNAs encoding mammalian cytosolic malate
RT   dehydrogenase. Comparison of the amino acid sequences of mammalian and
RT   bacterial malate dehydrogenase.";
RL   J. Biol. Chem. 262:15127-15131(1987).
RN   [3]
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), PARTIAL PROTEIN SEQUENCE, AND
RP   ACETYLATION AT SER-2.
RX   PubMed=3606987; DOI=10.1021/bi00384a011;
RA   Birktoft J.J., Bradshaw R.A., Banaszak L.J.;
RT   "Structure of porcine heart cytoplasmic malate dehydrogenase: combining X-
RT   ray diffraction and chemical sequence data in structural studies.";
RL   Biochemistry 26:2722-2734(1987).
RN   [4]
RP   X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2-334 IN COMPLEX WITH NAD, AND
RP   ACTIVE SITE.
RX   PubMed=2775751; DOI=10.1021/bi00440a051;
RA   Birktoft J.J., Rhodes G., Banaszak L.J.;
RT   "Refined crystal structure of cytoplasmic malate dehydrogenase at 2.5-A
RT   resolution.";
RL   Biochemistry 28:6065-6081(1989).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 2-334 IN COMPLEX WITH NAD AND
RP   SUBSTRATE ANALOG, AND SUBUNIT.
RX   PubMed=10075524; DOI=10.1006/jmbi.1998.2357;
RA   Chapman A.D., Cortes A., Dafforn T.R., Clarke A.R., Brady R.L.;
RT   "Structural basis of substrate specificity in malate dehydrogenases:
RT   crystal structure of a ternary complex of porcine cytoplasmic malate
RT   dehydrogenase, alpha-ketomalonate and tetrahydoNAD.";
RL   J. Mol. Biol. 285:703-712(1999).
CC   -!- FUNCTION: Catalyzes the reduction of aromatic alpha-keto acids in the
CC       presence of NADH. Plays essential roles in the malate-aspartate shuttle
CC       and the tricarboxylic acid cycle, important in mitochondrial NADH
CC       supply for oxidative phosphorylation. Catalyzes the reduction of 2-
CC       oxoglutarate to 2-hydroxyglutarate, leading to elevated reactive oxygen
CC       species (ROS). {ECO:0000250|UniProtKB:P40925}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(S)-malate + NAD(+) = H(+) + NADH + oxaloacetate;
CC         Xref=Rhea:RHEA:21432, ChEBI:CHEBI:15378, ChEBI:CHEBI:15589,
CC         ChEBI:CHEBI:16452, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.37;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21433;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:21434;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(2R)-2-hydroxy-3-(4-hydroxyphenyl)propanoate + NAD(+) = 3-(4-
CC         hydroxyphenyl)pyruvate + H(+) + NADH; Xref=Rhea:RHEA:10780,
CC         ChEBI:CHEBI:10980, ChEBI:CHEBI:15378, ChEBI:CHEBI:36242,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.96;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:10782;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(S)-2-hydroxyglutarate + NAD(+) = 2-oxoglutarate + H(+) +
CC         NADH; Xref=Rhea:RHEA:57172, ChEBI:CHEBI:15378, ChEBI:CHEBI:16782,
CC         ChEBI:CHEBI:16810, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:57174;
CC         Evidence={ECO:0000250|UniProtKB:P40925};
CC   -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:10075524}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000305|PubMed:8682322}.
CC   -!- PTM: ISGylated. {ECO:0000250|UniProtKB:P40925}.
CC   -!- PTM: Acetylation at Lys-118 dramatically enhances enzymatic activity
CC       and promotes adipogenic differentiation.
CC       {ECO:0000250|UniProtKB:P40925}.
CC   -!- SIMILARITY: Belongs to the LDH/MDH superfamily. MDH type 2 family.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Worthington enzyme manual;
CC       URL="https://www.worthington-biochem.com/MDH/";
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DR   EMBL; U44846; AAC48610.1; -; mRNA.
DR   EMBL; M29463; AAA31072.1; -; mRNA.
DR   PIR; JC4876; A32472.
DR   RefSeq; NP_999039.1; NM_213874.1.
DR   RefSeq; XP_013851563.1; XM_013996109.1.
DR   PDB; 4MDH; X-ray; 2.50 A; A/B=2-334.
DR   PDB; 5MDH; X-ray; 2.40 A; A/B=2-334.
DR   PDBsum; 4MDH; -.
DR   PDBsum; 5MDH; -.
DR   AlphaFoldDB; P11708; -.
DR   SMR; P11708; -.
DR   STRING; 9823.ENSSSCP00000062430; -.
DR   BindingDB; P11708; -.
DR   ChEMBL; CHEMBL4048; -.
DR   DrugCentral; P11708; -.
DR   iPTMnet; P11708; -.
DR   PaxDb; 9823-ENSSSCP00000021561; -.
DR   PeptideAtlas; P11708; -.
DR   Ensembl; ENSSSCT00000084364.1; ENSSSCP00000062212.1; ENSSSCG00000025751.4.
DR   Ensembl; ENSSSCT00005061167.1; ENSSSCP00005037807.1; ENSSSCG00005038108.1.
DR   Ensembl; ENSSSCT00005061204.1; ENSSSCP00005037838.1; ENSSSCG00005038108.1.
DR   Ensembl; ENSSSCT00015066598.1; ENSSSCP00015026700.1; ENSSSCG00015049456.1.
DR   Ensembl; ENSSSCT00015066818.1; ENSSSCP00015026794.1; ENSSSCG00015049456.1.
DR   Ensembl; ENSSSCT00025024872.1; ENSSSCP00025010511.1; ENSSSCG00025018263.1.
DR   Ensembl; ENSSSCT00025024902.1; ENSSSCP00025010522.1; ENSSSCG00025018263.1.
DR   Ensembl; ENSSSCT00030004373.1; ENSSSCP00030001739.1; ENSSSCG00030003287.1.
DR   Ensembl; ENSSSCT00030004398.1; ENSSSCP00030001751.1; ENSSSCG00030003287.1.
DR   Ensembl; ENSSSCT00035086982.1; ENSSSCP00035036265.1; ENSSSCG00035064600.1.
DR   Ensembl; ENSSSCT00035086994.1; ENSSSCP00035036275.1; ENSSSCG00035064600.1.
DR   Ensembl; ENSSSCT00045034851.1; ENSSSCP00045024175.1; ENSSSCG00045020269.1.
DR   Ensembl; ENSSSCT00045034956.1; ENSSSCP00045024253.1; ENSSSCG00045020269.1.
DR   Ensembl; ENSSSCT00055040807.1; ENSSSCP00055032460.1; ENSSSCG00055020633.1.
DR   Ensembl; ENSSSCT00055040984.1; ENSSSCP00055032609.1; ENSSSCG00055020633.1.
DR   Ensembl; ENSSSCT00060063466.1; ENSSSCP00060027214.1; ENSSSCG00060046704.1.
DR   Ensembl; ENSSSCT00060063473.1; ENSSSCP00060027217.1; ENSSSCG00060046704.1.
DR   Ensembl; ENSSSCT00065079812.1; ENSSSCP00065034720.1; ENSSSCG00065058308.1.
DR   Ensembl; ENSSSCT00065079828.1; ENSSSCP00065034726.1; ENSSSCG00065058308.1.
DR   Ensembl; ENSSSCT00070060652.1; ENSSSCP00070051692.1; ENSSSCG00070030148.1.
DR   Ensembl; ENSSSCT00070060672.1; ENSSSCP00070051712.1; ENSSSCG00070030148.1.
DR   GeneID; 396894; -.
DR   KEGG; ssc:396894; -.
DR   CTD; 4190; -.
DR   VGNC; VGNC:109461; MDH1.
DR   eggNOG; KOG1496; Eukaryota.
DR   GeneTree; ENSGT00530000063410; -.
DR   InParanoid; P11708; -.
DR   OMA; TKGMERG; -.
DR   OrthoDB; 501358at2759; -.
DR   BioCyc; MetaCyc:MONOMER-13033; -.
DR   Reactome; R-SSC-70263; Gluconeogenesis.
DR   SABIO-RK; P11708; -.
DR   EvolutionaryTrace; P11708; -.
DR   PRO; PR:P11708; -.
DR   Proteomes; UP000008227; Chromosome 3.
DR   Proteomes; UP000314985; Chromosome 3.
DR   Proteomes; UP000694570; Unplaced.
DR   Proteomes; UP000694571; Unplaced.
DR   Proteomes; UP000694720; Unplaced.
DR   Proteomes; UP000694722; Unplaced.
DR   Proteomes; UP000694723; Unplaced.
DR   Proteomes; UP000694724; Unplaced.
DR   Proteomes; UP000694725; Unplaced.
DR   Proteomes; UP000694726; Unplaced.
DR   Proteomes; UP000694727; Unplaced.
DR   Proteomes; UP000694728; Unplaced.
DR   Bgee; ENSSSCG00000025751; Expressed in occipital cortex and 42 other cell types or tissues.
DR   ExpressionAtlas; P11708; baseline and differential.
DR   GO; GO:0005829; C:cytosol; IDA:MGI.
DR   GO; GO:0047995; F:hydroxyphenylpyruvate reductase activity; IEA:RHEA.
DR   GO; GO:0030060; F:L-malate dehydrogenase activity; IBA:GO_Central.
DR   GO; GO:0051287; F:NAD binding; IDA:UniProtKB.
DR   GO; GO:0006108; P:malate metabolic process; IBA:GO_Central.
DR   GO; GO:0006734; P:NADH metabolic process; IBA:GO_Central.
DR   GO; GO:0006107; P:oxaloacetate metabolic process; IBA:GO_Central.
DR   GO; GO:0006099; P:tricarboxylic acid cycle; IBA:GO_Central.
DR   CDD; cd01336; MDH_cytoplasmic_cytosolic; 1.
DR   Gene3D; 3.90.110.10; Lactate dehydrogenase/glycoside hydrolase, family 4, C-terminal; 1.
DR   Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR   HAMAP; MF_01517; Malate_dehydrog_2; 1.
DR   InterPro; IPR001557; L-lactate/malate_DH.
DR   InterPro; IPR022383; Lactate/malate_DH_C.
DR   InterPro; IPR001236; Lactate/malate_DH_N.
DR   InterPro; IPR015955; Lactate_DH/Glyco_Ohase_4_C.
DR   InterPro; IPR001252; Malate_DH_AS.
DR   InterPro; IPR011274; Malate_DH_NAD-dep_euk.
DR   InterPro; IPR010945; Malate_DH_type2.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   NCBIfam; TIGR01759; MalateDH-SF1; 1.
DR   NCBIfam; TIGR01758; MDH_euk_cyt; 1.
DR   PANTHER; PTHR23382; MALATE DEHYDROGENASE; 1.
DR   PANTHER; PTHR23382:SF3; MALATE DEHYDROGENASE, CYTOPLASMIC; 1.
DR   Pfam; PF02866; Ldh_1_C; 1.
DR   Pfam; PF00056; Ldh_1_N; 1.
DR   PIRSF; PIRSF000102; Lac_mal_DH; 1.
DR   SUPFAM; SSF56327; LDH C-terminal domain-like; 1.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   PROSITE; PS00068; MDH; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Cytoplasm; Direct protein sequencing;
KW   Methylation; NAD; Oxidoreductase; Phosphoprotein; Reference proteome;
KW   Tricarboxylic acid cycle; Ubl conjugation.
FT   INIT_MET        1
FT                   /note="Removed"
FT   CHAIN           2..334
FT                   /note="Malate dehydrogenase, cytoplasmic"
FT                   /id="PRO_0000113411"
FT   ACT_SITE        187
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000305|PubMed:2775751"
FT   BINDING         11..17
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:10075524,
FT                   ECO:0000269|PubMed:2775751"
FT   BINDING         42
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:10075524,
FT                   ECO:0000269|PubMed:2775751"
FT   BINDING         92
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000305|PubMed:10075524"
FT   BINDING         98
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000305|PubMed:10075524"
FT   BINDING         105
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:10075524"
FT   BINDING         112
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:10075524"
FT   BINDING         129..131
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000269|PubMed:10075524,
FT                   ECO:0000269|PubMed:2775751"
FT   BINDING         131
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000305|PubMed:10075524"
FT   BINDING         162
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000305|PubMed:10075524"
FT   MOD_RES         2
FT                   /note="N-acetylserine"
FT                   /evidence="ECO:0000269|PubMed:3606987"
FT   MOD_RES         110
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         118
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P40925"
FT   MOD_RES         121
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P40925"
FT   MOD_RES         214
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         217
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         230
FT                   /note="Omega-N-methylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         241
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P40925"
FT   MOD_RES         298
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P40925"
FT   MOD_RES         298
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         309
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         318
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P14152"
FT   MOD_RES         332
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O88989"
FT   MOD_RES         333
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P40925"
FT   CONFLICT        238
FT                   /note="R -> Q (in Ref. 2; AAA31072)"
FT                   /evidence="ECO:0000305"
FT   STRAND          5..11
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           15..18
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           21..25
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   TURN            26..30
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          36..41
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           44..46
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           47..59
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          65..72
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           74..77
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   TURN            78..80
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          82..86
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   TURN            98..101
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           102..119
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          125..128
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          130..132
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           133..142
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           149..151
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          152..154
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           157..171
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           175..177
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          182..185
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          192..194
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          199..201
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          206..208
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           209..213
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           216..220
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           222..238
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           244..259
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          267..272
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          277..279
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          285..293
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   STRAND          296..299
FT                   /evidence="ECO:0007829|PDB:5MDH"
FT   HELIX           307..333
FT                   /evidence="ECO:0007829|PDB:5MDH"
SQ   SEQUENCE   334 AA;  36454 MW;  2574A8F3C2DD2C84 CRC64;
     MSEPIRVLVT GAAGQIAYSL LYSIGNGSVF GKDQPIILVL LDITPMMGVL DGVLMELQDC
     ALPLLKDVIA TDKEEIAFKD LDVAILVGSM PRRDGMERKD LLKANVKIFK CQGAALDKYA
     KKSVKVIVVG NPANTNCLTA SKSAPSIPKE NFSCLTRLDH NRAKAQIALK LGVTSDDVKN
     VIIWGNHSST QYPDVNHAKV KLQAKEVGVY EAVKDDSWLK GEFITTVQQR GAAVIKARKL
     SSAMSAAKAI CDHVRDIWFG TPEGEFVSMG IISDGNSYGV PDDLLYSFPV TIKDKTWKIV
     EGLPINDFSR EKMDLTAKEL AEEKETAFEF LSSA
//