ID   LDHD_HUMAN              Reviewed;         507 AA.
AC   Q86WU2; Q8IZK5;
DT   28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2003, sequence version 1.
DT   27-MAR-2024, entry version 160.
DE   RecName: Full=Probable D-lactate dehydrogenase, mitochondrial;
DE            Short=DLD;
DE            Short=Lactate dehydrogenase D;
DE            EC=1.1.2.4 {ECO:0000305|PubMed:30931947};
DE   Flags: Precursor;
GN   Name=LDHD {ECO:0000312|HGNC:HGNC:19708};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1] {ECO:0000305, ECO:0000312|EMBL:AAM50322.1}
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH CSRP3, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=12127981; DOI=10.1016/s0006-291x(02)00768-4;
RA   Flick M.J., Konieczny S.F.;
RT   "Identification of putative mammalian D-lactate dehydrogenase enzymes.";
RL   Biochem. Biophys. Res. Commun. 295:910-916(2002).
RN   [2] {ECO:0000305, ECO:0000312|EMBL:AAH40279.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Brain {ECO:0000312|EMBL:AAH47902.1}, and Colon
RC   {ECO:0000312|EMBL:AAH40279.1};
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [4]
RP   INVOLVEMENT IN DLACD, VARIANTS DLACD CYS-374 AND MET-463, AND FUNCTION.
RX   PubMed=30931947; DOI=10.1038/s41467-019-09458-6;
RA   Monroe G.R., van Eerde A.M., Tessadori F., Duran K.J., Savelberg S.M.C.,
RA   van Alfen J.C., Terhal P.A., van der Crabben S.N., Lichtenbelt K.D.,
RA   Fuchs S.A., Gerrits J., van Roosmalen M.J., van Gassen K.L.,
RA   van Aalderen M., Koot B.G., Oostendorp M., Duran M., Visser G.,
RA   de Koning T.J., Cali F., Bosco P., Geleijns K.,
RA   de Sain-van der Velden M.G.M., Knoers N.V., Bakkers J.,
RA   Verhoeven-Duif N.M., van Haaften G., Jans J.J.;
RT   "Identification of human D lactate dehydrogenase deficiency.";
RL   Nat. Commun. 10:1477-1477(2019).
CC   -!- FUNCTION: Involved in D-lactate, but not L-lactate catabolic process.
CC       {ECO:0000269|PubMed:30931947}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(R)-lactate + 2 Fe(III)-[cytochrome c] = 2 Fe(II)-[cytochrome
CC         c] + 2 H(+) + pyruvate; Xref=Rhea:RHEA:13521, Rhea:RHEA-COMP:10350,
CC         Rhea:RHEA-COMP:14399, ChEBI:CHEBI:15361, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16004, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034; EC=1.1.2.4;
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13522;
CC         Evidence={ECO:0000305|PubMed:30931947};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:P39976};
CC   -!- SUBUNIT: Interacts with CSRP3. {ECO:0000269|PubMed:12127981}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:Q7TNG8}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1 {ECO:0000269|PubMed:15489334};
CC         IsoId=Q86WU2-1; Sequence=Displayed;
CC       Name=2 {ECO:0000269|PubMed:12127981};
CC         IsoId=Q86WU2-2; Sequence=VSP_052253;
CC   -!- TISSUE SPECIFICITY: Expressed moderately in heart and liver and at
CC       lower levels in skeletal muscle and kidney.
CC       {ECO:0000269|PubMed:12127981}.
CC   -!- DISEASE: D-lactic aciduria with gout (DLACD) [MIM:245450]: An autosomal
CC       recessive metabolic disorder characterized by D-lactic aciduria in the
CC       presence of normal plasma lactic acid. {ECO:0000269|PubMed:30931947}.
CC       Note=The disease is caused by variants affecting the gene represented
CC       in this entry.
CC   -!- SIMILARITY: Belongs to the FAD-binding oxidoreductase/transferase type
CC       4 family. {ECO:0000255}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAM50322.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; AY092767; AAM50322.1; ALT_FRAME; mRNA.
DR   EMBL; BC040279; AAH40279.1; -; mRNA.
DR   EMBL; BC047902; AAH47902.1; -; mRNA.
DR   CCDS; CCDS10913.1; -. [Q86WU2-1]
DR   CCDS; CCDS45529.1; -. [Q86WU2-2]
DR   RefSeq; NP_705690.2; NM_153486.3. [Q86WU2-1]
DR   RefSeq; NP_919417.1; NM_194436.2. [Q86WU2-2]
DR   AlphaFoldDB; Q86WU2; -.
DR   SMR; Q86WU2; -.
DR   BioGRID; 128242; 99.
DR   IntAct; Q86WU2; 36.
DR   STRING; 9606.ENSP00000300051; -.
DR   iPTMnet; Q86WU2; -.
DR   PhosphoSitePlus; Q86WU2; -.
DR   SwissPalm; Q86WU2; -.
DR   BioMuta; LDHD; -.
DR   DMDM; 74727712; -.
DR   EPD; Q86WU2; -.
DR   jPOST; Q86WU2; -.
DR   MassIVE; Q86WU2; -.
DR   MaxQB; Q86WU2; -.
DR   PaxDb; 9606-ENSP00000300051; -.
DR   PeptideAtlas; Q86WU2; -.
DR   ProteomicsDB; 70205; -. [Q86WU2-1]
DR   ProteomicsDB; 70206; -. [Q86WU2-2]
DR   Antibodypedia; 30293; 275 antibodies from 28 providers.
DR   DNASU; 197257; -.
DR   Ensembl; ENST00000300051.8; ENSP00000300051.4; ENSG00000166816.15. [Q86WU2-1]
DR   Ensembl; ENST00000450168.3; ENSP00000417011.2; ENSG00000166816.15. [Q86WU2-2]
DR   GeneID; 197257; -.
DR   KEGG; hsa:197257; -.
DR   MANE-Select; ENST00000450168.3; ENSP00000417011.2; NM_194436.3; NP_919417.1. [Q86WU2-2]
DR   UCSC; uc002fdm.4; human. [Q86WU2-1]
DR   AGR; HGNC:19708; -.
DR   CTD; 197257; -.
DR   DisGeNET; 197257; -.
DR   GeneCards; LDHD; -.
DR   HGNC; HGNC:19708; LDHD.
DR   HPA; ENSG00000166816; Tissue enhanced (heart muscle, liver).
DR   MalaCards; LDHD; -.
DR   MIM; 245450; phenotype.
DR   MIM; 607490; gene.
DR   neXtProt; NX_Q86WU2; -.
DR   OpenTargets; ENSG00000166816; -.
DR   PharmGKB; PA134917525; -.
DR   VEuPathDB; HostDB:ENSG00000166816; -.
DR   eggNOG; KOG1231; Eukaryota.
DR   GeneTree; ENSGT00940000158705; -.
DR   HOGENOM; CLU_017779_3_0_1; -.
DR   InParanoid; Q86WU2; -.
DR   OMA; GQGFEWA; -.
DR   OrthoDB; 1664005at2759; -.
DR   PhylomeDB; Q86WU2; -.
DR   TreeFam; TF314122; -.
DR   BioCyc; MetaCyc:HS15490-MONOMER; -.
DR   BRENDA; 1.1.2.4; 2681.
DR   PathwayCommons; Q86WU2; -.
DR   Reactome; R-HSA-1268020; Mitochondrial protein import.
DR   SignaLink; Q86WU2; -.
DR   BioGRID-ORCS; 197257; 10 hits in 1150 CRISPR screens.
DR   GenomeRNAi; 197257; -.
DR   Pharos; Q86WU2; Tbio.
DR   PRO; PR:Q86WU2; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; Q86WU2; Protein.
DR   Bgee; ENSG00000166816; Expressed in apex of heart and 101 other cell types or tissues.
DR   ExpressionAtlas; Q86WU2; baseline and differential.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR   GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR   GO; GO:0004458; F:D-lactate dehydrogenase (cytochrome) activity; IBA:GO_Central.
DR   GO; GO:0008720; F:D-lactate dehydrogenase activity; IBA:GO_Central.
DR   GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR   GO; GO:0050660; F:flavin adenine dinucleotide binding; IBA:GO_Central.
DR   GO; GO:1903457; P:lactate catabolic process; IMP:UniProtKB.
DR   Gene3D; 3.30.465.10; -; 1.
DR   Gene3D; 3.30.70.2190; -; 1.
DR   Gene3D; 3.30.70.2740; -; 1.
DR   Gene3D; 3.30.43.10; Uridine Diphospho-n-acetylenolpyruvylglucosamine Reductase, domain 2; 1.
DR   InterPro; IPR004113; FAD-bd_oxidored_4_C.
DR   InterPro; IPR016166; FAD-bd_PCMH.
DR   InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR   InterPro; IPR016167; FAD-bd_PCMH_sub1.
DR   InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR   InterPro; IPR016164; FAD-linked_Oxase-like_C.
DR   InterPro; IPR006094; Oxid_FAD_bind_N.
DR   InterPro; IPR016171; Vanillyl_alc_oxidase_C-sub2.
DR   PANTHER; PTHR11748; D-LACTATE DEHYDROGENASE; 1.
DR   PANTHER; PTHR11748:SF111; D-LACTATE DEHYDROGENASE, MITOCHONDRIAL-RELATED; 1.
DR   Pfam; PF02913; FAD-oxidase_C; 1.
DR   Pfam; PF01565; FAD_binding_4; 1.
DR   SUPFAM; SSF56176; FAD-binding/transporter-associated domain-like; 1.
DR   SUPFAM; SSF55103; FAD-linked oxidases, C-terminal domain; 1.
DR   PROSITE; PS51387; FAD_PCMH; 1.
DR   Genevisible; Q86WU2; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Alternative splicing; Disease variant; FAD; Flavoprotein;
KW   Mitochondrion; Oxidoreductase; Reference proteome; Transit peptide.
FT   TRANSIT         1..52
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           53..507
FT                   /note="Probable D-lactate dehydrogenase, mitochondrial"
FT                   /id="PRO_0000262952"
FT   DOMAIN          62..265
FT                   /note="FAD-binding PCMH-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT   MOD_RES         36
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q7TNG8"
FT   MOD_RES         315
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q7TNG8"
FT   MOD_RES         358
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q7TNG8"
FT   MOD_RES         358
FT                   /note="N6-succinyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q7TNG8"
FT   MOD_RES         445
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q7TNG8"
FT   MOD_RES         472
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q7TNG8"
FT   VAR_SEQ         211..233
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12127981"
FT                   /id="VSP_052253"
FT   VARIANT         233
FT                   /note="R -> K (in dbSNP:rs11644820)"
FT                   /id="VAR_029561"
FT   VARIANT         374
FT                   /note="W -> C (in DLACD; probable enzymatic
FT                   loss-of-function; contrary to the wild-type protein, unable
FT                   to restore basal D-lactate levels when tested in knockout
FT                   zebrafish model; dbSNP:rs1567502487)"
FT                   /evidence="ECO:0000269|PubMed:30931947"
FT                   /id="VAR_082214"
FT   VARIANT         463
FT                   /note="T -> M (in DLACD; probable enzymatic
FT                   loss-of-function; contrary to the wild-type protein, unable
FT                   to restore basal D-lactate levels when tested in knockout
FT                   zebrafish model; dbSNP:rs764877688)"
FT                   /evidence="ECO:0000269|PubMed:30931947"
FT                   /id="VAR_082215"
FT   CONFLICT        323
FT                   /note="T -> I (in Ref. 1; AAM50322)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   507 AA;  54871 MW;  5625743709939182 CRC64;
     MARLLRSATW ELFPWRGYCS QKAKGELCRD FVEALKAVVG GSHVSTAAVV REQHGRDESV
     HRCEPPDAVV WPQNVEQVSR LAALCYRQGV PIIPFGTGTG LEGGVCAVQG GVCVNLTHMD
     RILELNQEDF SVVVEPGVTR KALNAHLRDS GLWFPVDPGA DASLCGMAAT GASGTNAVRY
     GTMRDNVLNL EVVLPDGRLL HTAGRGRHFR FGFWPEIPHH TAWYSPCVSL GRRKSAAGYN
     LTGLFVGSEG TLGLITATTL RLHPAPEATV AATCAFPSVQ AAVDSTVHIL QAAVPVARIE
     FLDEVMMDAC NRYSKLNCLV APTLFLEFHG SQQALEEQLQ RTEEIVQQNG ASDFSWAKEA
     EERSRLWTAR HNAWYAALAT RPGCKGYSTD VCVPISRLPE IVVQTKEDLN ASGLTGSIVG
     HVGDGNFHCI LLVNPDDAEE LGRVKAFAEQ LGRRALALHG TCTGEHGIGM GKRQLLQEEV
     GAVGVETMRQ LKAVLDPQGL MNPGKVL
//