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 27-MAR-2024, entry version 183. 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 = 2 5'- CC deoxyadenosine + [[Fe-S] cluster scaffold protein] + 4 Fe(3+) + 2 CC hydrogen sulfide + 2 L-methionine + N(6)-[(R)-dihydrolipoyl]-L-lysyl- CC [protein] + 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 39. DR IntAct; O43766; 1. DR MINT; O43766; -. DR STRING; 9606.ENSP00000492260; -. 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; 9606-ENSP00000261434; -. DR PeptideAtlas; O43766; -. DR ProteomicsDB; 49157; -. [O43766-1] DR ProteomicsDB; 9588; -. DR Pumba; O43766; -. DR TopDownProteomics; O43766-2; -. [O43766-2] DR Antibodypedia; 11693; 137 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 AGR; HGNC:16429; -. 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 OrthoDB; 575at2759; -. DR PhylomeDB; O43766; -. DR TreeFam; TF300817; -. DR BioCyc; MetaCyc:HS04528-MONOMER; -. DR PathwayCommons; O43766; -. DR Reactome; R-HSA-389661; Glyoxylate metabolism and glycine degradation. DR SignaLink; O43766; -. DR UniPathway; UPA00538; UER00593. DR BioGRID-ORCS; 11019; 298 hits in 1158 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 primordial germ cell in gonad and 173 other cell types or tissues. DR ExpressionAtlas; O43766; baseline and differential. 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: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:0032496; P:response to lipopolysaccharide; ISS:UniProtKB. DR GO; GO:0006979; P:response to oxidative stress; ISS:UniProtKB. DR CDD; cd01335; Radical_SAM; 1. DR Gene3D; 3.20.20.70; Aldolase class I; 1. DR HAMAP; MF_00206; Lipoyl_synth; 1. DR InterPro; IPR013785; Aldolase_TIM. DR InterPro; IPR006638; Elp3/MiaA/NifB-like_rSAM. DR InterPro; IPR031691; LIAS_N. DR InterPro; IPR003698; Lipoyl_synth. DR InterPro; IPR007197; rSAM. DR NCBIfam; TIGR00510; lipA; 1. DR PANTHER; PTHR10949; LIPOYL SYNTHASE; 1. DR PANTHER; PTHR10949:SF0; LIPOYL SYNTHASE, MITOCHONDRIAL; 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 SUPFAM; SSF102114; Radical SAM enzymes; 1. DR PROSITE; PS51918; RADICAL_SAM; 1. DR Genevisible; O43766; HS. 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 //