LDHD_HUMAN
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 03-AUG-2022, entry version 151.
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
RC Colon {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 BioGRID; 128242; 99.
DR IntAct; Q86WU2; 36.
DR STRING; 9606.ENSP00000300051; -.
DR iPTMnet; Q86WU2; -.
DR PhosphoSitePlus; Q86WU2; -.
DR BioMuta; LDHD; -.
DR DMDM; 74727712; -.
DR EPD; Q86WU2; -.
DR jPOST; Q86WU2; -.
DR MassIVE; Q86WU2; -.
DR MaxQB; Q86WU2; -.
DR PaxDb; Q86WU2; -.
DR PeptideAtlas; Q86WU2; -.
DR PRIDE; Q86WU2; -.
DR ProteomicsDB; 70205; -. [Q86WU2-1]
DR ProteomicsDB; 70206; -. [Q86WU2-2]
DR Antibodypedia; 30293; 238 antibodies from 27 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 CTD; 197257; -.
DR DisGeNET; 197257; -.
DR GeneCards; LDHD; -.
DR HGNC; HGNC:19708; LDHD.
DR HPA; ENSG00000166816; Tissue enhanced (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; TPRTCGE; -.
DR OrthoDB; 824020at2759; -.
DR PhylomeDB; Q86WU2; -.
DR TreeFam; TF314122; -.
DR BioCyc; MetaCyc:HS15490-MON; -.
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 1071 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 99 other tissues.
DR ExpressionAtlas; Q86WU2; baseline and differential.
DR Genevisible; Q86WU2; HS.
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; 1.10.45.10; -; 1.
DR Gene3D; 3.30.43.10; -; 1.
DR Gene3D; 3.30.465.10; -; 1.
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; IPR004113; FAD-linked_oxidase_C.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR InterPro; IPR016171; Vanillyl_alc_oxidase_C-sub2.
DR Pfam; PF02913; FAD-oxidase_C; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF55103; SSF55103; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
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 loss-of-
FT function; contrary to the wild-type protein, unable to
FT 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 loss-of-
FT function; contrary to the wild-type protein, unable to
FT 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
