LIAS_HUMAN
ID LIAS_HUMAN Reviewed; 372 AA.
AC O43766; A8K873; C9JCF6; Q8IV62;
DT 10-OCT-2002, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 3.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Lipoyl synthase, mitochondrial {ECO:0000255|HAMAP-Rule:MF_03123};
DE EC=2.8.1.8 {ECO:0000255|HAMAP-Rule:MF_03123};
DE AltName: Full=Lipoate synthase {ECO:0000255|HAMAP-Rule:MF_03123};
DE Short=LS {ECO:0000255|HAMAP-Rule:MF_03123};
DE Short=Lip-syn {ECO:0000255|HAMAP-Rule:MF_03123};
DE AltName: Full=Lipoic acid synthase {ECO:0000255|HAMAP-Rule:MF_03123};
DE Flags: Precursor;
GN Name=LIAS {ECO:0000255|HAMAP-Rule:MF_03123}; Synonyms=LAS;
GN ORFNames=HUSSY-01;
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]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 260-372 (ISOFORM 1).
RX PubMed=11124703;
RX DOI=10.1002/1097-0061(200101)18:1<69::aid-yea647>3.0.co;2-h;
RA Stanchi F., Bertocco E., Toppo S., Dioguardi R., Simionati B., Cannata N.,
RA Zimbello R., Lanfranchi G., Valle G.;
RT "Characterization of 16 novel human genes showing high similarity to yeast
RT sequences.";
RL Yeast 18:69-80(2001).
RN [6]
RP VARIANT HGCLAS HIS-249.
RX PubMed=22152680; DOI=10.1016/j.ajhg.2011.11.011;
RA Mayr J.A., Zimmermann F.A., Fauth C., Bergheim C., Meierhofer D.,
RA Radmayr D., Zschocke J., Koch J., Sperl W.;
RT "Lipoic acid synthetase deficiency causes neonatal-onset epilepsy,
RT defective mitochondrial energy metabolism, and glycine elevation.";
RL Am. J. Hum. Genet. 89:792-797(2011).
CC -!- FUNCTION: Catalyzes the radical-mediated insertion of two sulfur atoms
CC into the C-6 and C-8 positions of the octanoyl moiety bound to the
CC lipoyl domains of lipoate-dependent enzymes, thereby converting the
CC octanoylated domains into lipoylated derivatives. {ECO:0000255|HAMAP-
CC Rule:MF_03123}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[[Fe-S] cluster scaffold protein carrying a second [4Fe-
CC 4S](2+) cluster] + 4 H(+) + N(6)-octanoyl-L-lysyl-[protein] + 2
CC oxidized [2Fe-2S]-[ferredoxin] + 2 S-adenosyl-L-methionine = (R)-
CC N(6)-dihydrolipoyl-L-lysyl-[protein] + 2 5'-deoxyadenosine + [[Fe-S]
CC cluster scaffold protein] + 4 Fe(3+) + 2 hydrogen sulfide + 2 L-
CC methionine + 2 reduced [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:16585,
CC Rhea:RHEA-COMP:9928, Rhea:RHEA-COMP:10000, Rhea:RHEA-COMP:10001,
CC Rhea:RHEA-COMP:10475, Rhea:RHEA-COMP:14568, Rhea:RHEA-COMP:14569,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17319, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:29919, ChEBI:CHEBI:33722, ChEBI:CHEBI:33737,
CC ChEBI:CHEBI:33738, ChEBI:CHEBI:57844, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:78809, ChEBI:CHEBI:83100; EC=2.8.1.8;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03123};
CC -!- COFACTOR:
CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03123};
CC Note=Binds 2 [4Fe-4S] clusters per subunit. One cluster is coordinated
CC with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
CC {ECO:0000255|HAMAP-Rule:MF_03123};
CC -!- PATHWAY: Protein modification; protein lipoylation via endogenous
CC pathway; protein N(6)-(lipoyl)lysine from octanoyl-[acyl-carrier-
CC protein]: step 2/2. {ECO:0000255|HAMAP-Rule:MF_03123}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000255|HAMAP-Rule:MF_03123}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O43766-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O43766-2; Sequence=VSP_047380, VSP_047381;
CC Name=3;
CC IsoId=O43766-3; Sequence=VSP_054764;
CC -!- DISEASE: Hyperglycinemia, lactic acidosis, and seizures (HGCLAS)
CC [MIM:614462]: An enzymatic defect resulting in an autosomal recessive
CC disorder of mitochondrial metabolism. It is characterized by early-
CC onset lactic acidosis, severe encephalomyopathy, and a pyruvate
CC oxidation defect. Affected individuals have neonatal-onset epilepsy,
CC poor growth, psychomotor retardation, muscular hypotonia, lactic
CC acidosis, and elevated glycine concentration in plasma and urine.
CC {ECO:0000269|PubMed:22152680}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the radical SAM superfamily. Lipoyl synthase
CC family. {ECO:0000255|HAMAP-Rule:MF_03123}.
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DR EMBL; AK292238; BAF84927.1; -; mRNA.
DR EMBL; AC021148; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471069; EAW92932.1; -; Genomic_DNA.
DR EMBL; BC023635; AAH23635.1; -; mRNA.
DR EMBL; AJ224162; CAA11859.1; -; mRNA.
DR CCDS; CCDS3453.1; -. [O43766-1]
DR CCDS; CCDS3454.1; -. [O43766-2]
DR CCDS; CCDS63950.1; -. [O43766-3]
DR RefSeq; NP_001265519.1; NM_001278590.1. [O43766-3]
DR RefSeq; NP_001265520.1; NM_001278591.1.
DR RefSeq; NP_001265521.1; NM_001278592.1.
DR RefSeq; NP_006850.2; NM_006859.3. [O43766-1]
DR RefSeq; NP_919433.1; NM_194451.2. [O43766-2]
DR AlphaFoldDB; O43766; -.
DR SMR; O43766; -.
DR BioGRID; 116209; 35.
DR STRING; 9606.ENSP00000261434; -.
DR DrugBank; DB00166; Lipoic acid.
DR iPTMnet; O43766; -.
DR PhosphoSitePlus; O43766; -.
DR BioMuta; LIAS; -.
DR EPD; O43766; -.
DR jPOST; O43766; -.
DR MassIVE; O43766; -.
DR MaxQB; O43766; -.
DR PaxDb; O43766; -.
DR PeptideAtlas; O43766; -.
DR PRIDE; O43766; -.
DR ProteomicsDB; 49157; -. [O43766-1]
DR ProteomicsDB; 9588; -.
DR TopDownProteomics; O43766-2; -. [O43766-2]
DR Antibodypedia; 11693; 122 antibodies from 25 providers.
DR DNASU; 11019; -.
DR Ensembl; ENST00000340169.7; ENSP00000340676.2; ENSG00000121897.15. [O43766-2]
DR Ensembl; ENST00000381846.2; ENSP00000371270.1; ENSG00000121897.15. [O43766-3]
DR Ensembl; ENST00000640888.2; ENSP00000492260.1; ENSG00000121897.15. [O43766-1]
DR GeneID; 11019; -.
DR KEGG; hsa:11019; -.
DR MANE-Select; ENST00000640888.2; ENSP00000492260.1; NM_006859.4; NP_006850.2.
DR UCSC; uc003guf.5; human. [O43766-1]
DR CTD; 11019; -.
DR DisGeNET; 11019; -.
DR GeneCards; LIAS; -.
DR HGNC; HGNC:16429; LIAS.
DR HPA; ENSG00000121897; Low tissue specificity.
DR MalaCards; LIAS; -.
DR MIM; 607031; gene.
DR MIM; 614462; phenotype.
DR neXtProt; NX_O43766; -.
DR OpenTargets; ENSG00000121897; -.
DR Orphanet; 401859; Lipoic acid synthetase deficiency.
DR PharmGKB; PA30369; -.
DR VEuPathDB; HostDB:ENSG00000121897; -.
DR eggNOG; KOG2672; Eukaryota.
DR GeneTree; ENSGT00390000006234; -.
DR HOGENOM; CLU_033144_2_0_1; -.
DR InParanoid; O43766; -.
DR OMA; PYCDIDF; -.
DR PhylomeDB; O43766; -.
DR TreeFam; TF300817; -.
DR PathwayCommons; O43766; -.
DR Reactome; R-HSA-389661; Glyoxylate metabolism and glycine degradation.
DR SignaLink; O43766; -.
DR UniPathway; UPA00538; UER00593.
DR BioGRID-ORCS; 11019; 274 hits in 1080 CRISPR screens.
DR ChiTaRS; LIAS; human.
DR GenomeRNAi; 11019; -.
DR Pharos; O43766; Tbio.
DR PRO; PR:O43766; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O43766; protein.
DR Bgee; ENSG00000121897; Expressed in hindlimb stylopod muscle and 171 other tissues.
DR ExpressionAtlas; O43766; baseline and differential.
DR Genevisible; O43766; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IEA:UniProtKB-UniRule.
DR GO; GO:0016992; F:lipoate synthase activity; ISS:UniProtKB.
DR GO; GO:0102552; F:lipoyl synthase activity (acting on glycine-cleavage complex H protein; IEA:UniProtKB-EC.
DR GO; GO:0102553; F:lipoyl synthase activity (acting on pyruvate dehydrogenase E2 protein); IEA:UniProtKB-EC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006954; P:inflammatory response; ISS:UniProtKB.
DR GO; GO:0009107; P:lipoate biosynthetic process; ISS:UniProtKB.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0009249; P:protein lipoylation; IEA:UniProtKB-UniRule.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0006979; P:response to oxidative stress; ISS:UniProtKB.
DR Gene3D; 3.20.20.70; -; 1.
DR HAMAP; MF_00206; Lipoyl_synth; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR006638; Elp3/MiaB/NifB.
DR InterPro; IPR031691; LIAS_N.
DR InterPro; IPR003698; Lipoyl_synth.
DR InterPro; IPR007197; rSAM.
DR PANTHER; PTHR10949; PTHR10949; 1.
DR Pfam; PF16881; LIAS_N; 1.
DR Pfam; PF04055; Radical_SAM; 1.
DR PIRSF; PIRSF005963; Lipoyl_synth; 1.
DR SFLD; SFLDF00271; lipoyl_synthase; 1.
DR SFLD; SFLDS00029; Radical_SAM; 1.
DR SMART; SM00729; Elp3; 1.
DR TIGRFAMs; TIGR00510; lipA; 1.
DR PROSITE; PS51918; RADICAL_SAM; 1.
PE 1: Evidence at protein level;
KW 4Fe-4S; Alternative splicing; Disease variant; Iron; Iron-sulfur;
KW Metal-binding; Mitochondrion; Reference proteome; S-adenosyl-L-methionine;
KW Transferase; Transit peptide.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT CHAIN 28..372
FT /note="Lipoyl synthase, mitochondrial"
FT /id="PRO_0000017723"
FT DOMAIN 122..341
FT /note="Radical SAM core"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01266"
FT BINDING 106
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT BINDING 111
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT BINDING 117
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT BINDING 137
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /ligand_note="4Fe-4S-S-AdoMet"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT BINDING 141
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /ligand_note="4Fe-4S-S-AdoMet"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT BINDING 144
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /ligand_note="4Fe-4S-S-AdoMet"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT BINDING 352
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03123"
FT VAR_SEQ 203..245
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_054764"
FT VAR_SEQ 320..322
FT /note="EEY -> NFS (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_047380"
FT VAR_SEQ 323..372
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_047381"
FT VARIANT 249
FT /note="R -> H (in HGCLAS; dbSNP:rs144133667)"
FT /evidence="ECO:0000269|PubMed:22152680"
FT /id="VAR_067839"
FT CONFLICT 253
FT /note="A -> V (in Ref. 4; AAH23635)"
FT /evidence="ECO:0000305"
FT CONFLICT 260
FT /note="R -> G (in Ref. 5; CAA11859)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 372 AA; 41911 MW; A5BEACA1F36CEB74 CRC64;
MSLRCGDAAR TLGPRVFGRY FCSPVRPLSS LPDKKKELLQ NGPDLQDFVS GDLADRSTWD
EYKGNLKRQK GERLRLPPWL KTEIPMGKNY NKLKNTLRNL NLHTVCEEAR CPNIGECWGG
GEYATATATI MLMGDTCTRG CRFCSVKTAR NPPPLDASEP YNTAKAIAEW GLDYVVLTSV
DRDDMPDGGA EHIAKTVSYL KERNPKILVE CLTPDFRGDL KAIEKVALSG LDVYAHNVET
VPELQSKVRD PRANFDQSLR VLKHAKKVQP DVISKTSIML GLGENDEQVY ATMKALREAD
VDCLTLGQYM QPTRRHLKVE EYITPEKFKY WEKVGNELGF HYTASGPLVR SSYKAGEFFL
KNLVAKRKTK DL
