ID HEMH_HUMAN Reviewed; 423 AA. AC P22830; A8KA72; Q8IXN1; Q8NAN0; DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot. DT 10-MAY-2005, sequence version 2. DT 27-MAR-2024, entry version 230. DE RecName: Full=Ferrochelatase, mitochondrial; DE EC=4.98.1.1 {ECO:0000269|PubMed:27599036, ECO:0000269|PubMed:8276824}; DE AltName: Full=Heme synthase; DE AltName: Full=Protoheme ferro-lyase; DE Flags: Precursor; GN Name=FECH {ECO:0000312|HGNC:HGNC:3647}; 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 [MRNA] (ISOFORM 1), AND VARIANT GLN-96. RX PubMed=2260980; DOI=10.1016/s0006-291x(05)80099-3; RA Nakahashi Y., Taketani S., Okuda M., Inoue K., Tokunaga R.; RT "Molecular cloning and sequence analysis of cDNA encoding human RT ferrochelatase."; RL Biochem. Biophys. Res. Commun. 173:748-755(1990). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLN-96. RA Gouya L.M., Martin C., Deybach J.-C., Puy H.V.; RT "Ferrochelatase: complete human gene sequence, amplifiable polymorphisms RT and molecular study of 12 families with erythropoietic protoporphyria."; RL Submitted (OCT-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Placenta, and Trachea; 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 [5] 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; 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 [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22. RX PubMed=7983009; DOI=10.1016/s0021-9258(18)47351-6; RA Tugores A., Magness S.T., Brenner D.A.; RT "A single promoter directs both housekeeping and erythroid preferential RT expression of the human ferrochelatase gene."; RL J. Biol. Chem. 269:30789-30797(1994). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22. RA Di Pierro E., Martinez di Montemuros F., Moriondo V., Cappellini M.D.; RT "Molecular analysis of ferrochelatase gene in erythropoietic RT protoporphyria."; RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases. RN [9] RP CHARACTERIZATION, MUTAGENESIS, FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=8276824; DOI=10.1016/s0021-9258(17)42362-3; RA Dailey H.A., Sellers V.M., Dailey T.A.; RT "Mammalian ferrochelatase. Expression and characterization of normal and RT two human protoporphyric ferrochelatases."; RL J. Biol. Chem. 269:390-395(1994). RN [10] RP IDENTIFICATION OF CYSTEINES COORDINATING THE 2FE-2S CLUSTER. RX PubMed=8973195; DOI=10.1021/bi9620114; RA Crouse B.R., Sellers V.M., Finnegan M.G., Dailey H.A., Johnson M.K.; RT "Site-directed mutagenesis and spectroscopic characterization of human RT ferrochelatase: identification of residues coordinating the [2Fe-2S] RT cluster."; RL Biochemistry 35:16222-16229(1996). RN [11] RP IDENTIFICATION OF CYSTEINES COORDINATING THE 2FE-2S CLUSTER. RX PubMed=9712849; DOI=10.1074/jbc.273.35.22311; RA Sellers V.M., Wang K.-F., Johnson M.K., Dailey H.A.; RT "Evidence that the fourth ligand to the 2Fe-2S cluster in animal RT ferrochelatase is a cysteine. Characterization of the enzyme from RT Drosophila melanogaster."; RL J. Biol. Chem. 273:22311-22316(1998). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [13] 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 [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [15] RP FUNCTION, INTERACTION WITH PGRMC1, MUTAGENESIS OF PHE-110, AND CATALYTIC RP ACTIVITY. RX PubMed=27599036; DOI=10.1021/acs.biochem.6b00756; RA Piel R.B. III, Shiferaw M.T., Vashisht A.A., Marcero J.R., Praissman J.L., RA Phillips J.D., Wohlschlegel J.A., Medlock A.E.; RT "A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A RT Partner and Regulator of Ferrochelatase."; RL Biochemistry 55:5204-5217(2016). RN [16] RP INTERACTION WITH ABCB7 AND ABCB10, AND SUBUNIT. RX PubMed=30765471; DOI=10.3324/haematol.2018.214320; RA Maio N., Kim K.S., Holmes-Hampton G., Singh A., Rouault T.A.; RT "Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an RT architecturally defined molecular complex required for heme biosynthesis."; RL Haematologica 104:1756-1767(2019). RN [17] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS). RX PubMed=11175906; DOI=10.1038/84152; RA Wu C.-K., Dailey H.A., Rose J.P., Burden A., Sellers V.M., Wang B.-C.; RT "The 2.0 A structure of human ferrochelatase, the terminal enzyme of heme RT biosynthesis."; RL Nat. Struct. Biol. 8:156-160(2001). RN [18] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 65-423 ALONE AND IN COMPLEX WITH RP PROTOPORPHYRIN IX, SUBUNIT, AND IRON-SULFUR CLUSTER. RX PubMed=17261801; DOI=10.1073/pnas.0606144104; RA Medlock A., Swartz L., Dailey T.A., Dailey H.A., Lanzilotta W.N.; RT "Substrate interactions with human ferrochelatase."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1789-1793(2007). RN [19] RP REVIEW ON VARIANTS EPP1. RX PubMed=9211198; DOI=10.1023/a:1005317124985; RA Cox T.M.; RT "Erythropoietic protoporphyria."; RL J. Inherit. Metab. Dis. 20:258-269(1997). RN [20] RP VARIANTS EPP1 CYS-55 AND ILE-267. RX PubMed=1755842; DOI=10.1016/0006-291x(91)91231-z; RA Lamoril J., Boulechfar S., de Verneuil H., Grandchamp B., Nordmann Y., RA Deybach J.-C.; RT "Human erythropoietic protoporphyria: two point mutations in the RT ferrochelatase gene."; RL Biochem. Biophys. Res. Commun. 181:594-599(1991). RN [21] RP VARIANT EPP1 SER-417. RX PubMed=1376018; RA Brenner D.A., Didier J.M., Frasier F., Christensen S.R., Evans G.A., RA Dailey H.A.; RT "A molecular defect in human protoporphyria."; RL Am. J. Hum. Genet. 50:1203-1210(1992). RN [22] RP VARIANT EPP1 GLY-362. RX PubMed=7910885; DOI=10.1016/s0140-6736(94)92525-9; RA Sarkany R.P.E., Alexander G.J.M.A., Cox T.M.; RT "Recessive inheritance of erythropoietic protoporphyria with liver RT failure."; RL Lancet 343:1394-1396(1994). RN [23] RP VARIANT EPP1 THR-186. RX PubMed=8757534; DOI=10.1046/j.1365-2141.1996.d01-1771.x; RA Imoto S., Tanizawa Y., Sata Y., Kaku K., Oka Y.; RT "A novel mutation in the ferrochelatase gene associated with erythropoietic RT protoporphyria."; RL Br. J. Haematol. 94:191-197(1996). RN [24] RP VARIANTS EPP1 LYS-71; PRO-151; HIS-191; THR-192; ILE-283; LYS-288; LEU-334 RP AND PHE-417 DEL, AND CHARACTERIZATION OF VARIANTS EPP1 LYS-71; PRO-151; RP HIS-191; THR-192; ILE-283; LYS-288; LEU-334 AND PHE-417 DEL. RX PubMed=9585598; DOI=10.1086/301870; RA Ruefenacht U.B., Gouya L., Schneider-Yin X., Puy H., Schaefer B.W., RA Aquaron R., Nordmann Y., Minder E.I., Deybach J.-C.; RT "Systematic analysis of molecular defects in the ferrochelatase gene from RT patients with erythropoietic protoporphyria."; RL Am. J. Hum. Genet. 62:1341-1352(1998). RN [25] RP VARIANT EPP1 PRO-386. RX PubMed=9740232; DOI=10.1046/j.1523-1747.1998.00327.x; RA Gouya L., Schneider-Yin X., Rufenacht U., Herrero C., Lecha M., RA Mascaro J.M., Puy H., Deybach J.-C., Minder E.I.; RT "Mutations in the ferrochelatase gene of four Spanish patients with RT erythropoietic protoporphyria."; RL J. Invest. Dermatol. 111:406-409(1998). RN [26] RP VARIANTS EPP1 SER-406; TYR-406 AND 408-ASN--CYS-411 DELINS LYS-SER-VAL-GLY, RP AND CHARACTERIZATION OF VARIANTS EPP1 SER-406; TYR-406 AND 408-ASN--CYS-411 RP DELINS LYS-SER-VAL-GLY. RX PubMed=10942404; RA Schneider-Yin X., Gouya L., Dorsey M., Ruefenacht U., Deybach J.-C., RA Ferreira G.C.; RT "Mutations in the iron-sulfur cluster ligands of the human ferrochelatase RT lead to erythropoietic protoporphyria."; RL Blood 96:1545-1549(2000). RN [27] RP VARIANT EPP1 ARG-182, AND CHARACTERIZATION OF VARIANT EPP1 ARG-182. RX PubMed=11375302; RA Ruefenacht U.B., Gregor A., Gouya L., Tarczynska-Nosal S., RA Schneider-Yin X., Deybach J.-C.; RT "New missense mutation in the human ferrochelatase gene in a family with RT erythropoietic protoporphyria: functional studies and correlation of RT genotype and phenotype."; RL Clin. Chem. 47:1112-1113(2001). RN [28] RP VARIANT EPP1 ARG-62. RX PubMed=12063482; DOI=10.1067/mjd.2002.120460; RA Poh-Fitzpatrick M.B., Wang X., Anderson K.E., Bloomer J.R., Bolwell B., RA Lichtin A.E.; RT "Erythropoietic protoporphyria: altered phenotype after bone marrow RT transplantation for myelogenous leukemia in a patient heteroallelic for RT ferrochelatase gene mutations."; RL J. Am. Acad. Dermatol. 46:861-866(2002). RN [29] RP VARIANTS EPP1 LYS-178 AND LEU-334. RX PubMed=12601550; DOI=10.1007/s100380300009; RA Wiman A., Floderus Y., Harper P.; RT "Novel mutations and phenotypic effect of the splice site modulator IVS3- RT 48C in nine Swedish families with erythropoietic protoporphyria."; RL J. Hum. Genet. 48:70-76(2003). RN [30] RP VARIANTS EPP1 LEU-139; TYR-236; LEU-260 AND ASN-379, AND CHARACTERIZATION RP OF VARIANTS EPP1 LEU-139; TYR-236; LEU-260 AND ASN-379. RX PubMed=15286165; DOI=10.1136/jmg.2003.016121; RA Whatley S.D., Mason N.G., Khan M., Zamiri M., Badminton M.N., RA Missaoui W.N., Dailey T.A., Dailey H.A., Douglas W.S., Wainwright N.J., RA Elder G.H.; RT "Autosomal recessive erythropoietic protoporphyria in the United Kingdom: RT prevalence and relationship to liver disease."; RL J. Med. Genet. 41:E105-E105(2004). RN [31] RP VARIANT EPP1 LEU-264. RX PubMed=17196862; DOI=10.1016/j.ymgme.2006.10.012; RA Aurizi C., Schneider-Yin X., Sorge F., Macri A., Minder E.I., Biolcati G.; RT "Heterogeneity of mutations in the ferrochelatase gene in Italian patients RT with erythropoietic protoporphyria."; RL Mol. Genet. Metab. 90:402-407(2007). CC -!- FUNCTION: Catalyzes the ferrous insertion into protoporphyrin IX. CC {ECO:0000269|PubMed:27599036, ECO:0000269|PubMed:8276824}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 H(+) + heme b = Fe(2+) + protoporphyrin IX; CC Xref=Rhea:RHEA:22584, ChEBI:CHEBI:15378, ChEBI:CHEBI:29033, CC ChEBI:CHEBI:57306, ChEBI:CHEBI:60344; EC=4.98.1.1; CC Evidence={ECO:0000269|PubMed:27599036, ECO:0000269|PubMed:8276824}; CC -!- COFACTOR: CC Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135; CC Note=Binds 1 [2Fe-2S] cluster. {ECO:0000269|PubMed:8276824}; CC -!- ACTIVITY REGULATION: Inhibited by nitric oxide (NO). The 2Fe-2S cluster CC could act as a NO sensor. CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoheme CC biosynthesis; protoheme from protoporphyrin-IX: step 1/1. CC -!- SUBUNIT: Homodimer (PubMed:17261801, PubMed:30765471). Interacts with CC PGRMC1; the interaction results in decreased FECH activity CC (PubMed:27599036). Interacts with ABCB10 and SLC25A37; this interaction CC forms an oligomeric complex (By similarity). Forms a complex with ABCB7 CC and ABCB10, where a dimeric FECH bridges ABCB7 and ABCB10 homodimers; CC this complex may be required for cellular iron homeostasis, CC mitochondrial function and heme biosynthesis (PubMed:30765471). CC Interacts with ABCB7 and ABCB10 (PubMed:30765471). CC {ECO:0000250|UniProtKB:P22315, ECO:0000269|PubMed:17261801, CC ECO:0000269|PubMed:27599036, ECO:0000269|PubMed:30765471}. CC -!- INTERACTION: CC P22830; Q9NRK6: ABCB10; NbExp=2; IntAct=EBI-1390356, EBI-6164528; CC P22830; O75027: ABCB7; NbExp=9; IntAct=EBI-1390356, EBI-1236950; CC P22830; P22830: FECH; NbExp=4; IntAct=EBI-1390356, EBI-1390356; CC P22830; O00264: PGRMC1; NbExp=3; IntAct=EBI-1390356, EBI-1045534; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane; Peripheral membrane CC protein; Matrix side. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P22830-1; Sequence=Displayed; CC Name=2; CC IsoId=P22830-2; Sequence=VSP_041208; CC -!- DISEASE: Protoporphyria, erythropoietic, 1 (EPP1) [MIM:177000]: An CC autosomal recessive form of porphyria with onset usually before age 10 CC years. Porphyrias are inherited defects in the biosynthesis of heme, CC resulting in the accumulation and increased excretion of porphyrins or CC porphyrin precursors. They are classified as erythropoietic or hepatic, CC depending on whether the enzyme deficiency occurs in red blood cells or CC in the liver. Erythropoietic protoporphyria is marked by excessive CC protoporphyrin in erythrocytes, plasma, liver and feces, and by widely CC varying photosensitive skin changes ranging from a burning or pruritic CC sensation to erythema, edema and wheals. {ECO:0000269|PubMed:10942404, CC ECO:0000269|PubMed:11375302, ECO:0000269|PubMed:12063482, CC ECO:0000269|PubMed:12601550, ECO:0000269|PubMed:1376018, CC ECO:0000269|PubMed:15286165, ECO:0000269|PubMed:17196862, CC ECO:0000269|PubMed:1755842, ECO:0000269|PubMed:7910885, CC ECO:0000269|PubMed:8757534, ECO:0000269|PubMed:9211198, CC ECO:0000269|PubMed:9585598, ECO:0000269|PubMed:9740232}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the ferrochelatase family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ferrochelatase entry; CC URL="https://en.wikipedia.org/wiki/Ferrochelatase"; 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; D00726; BAA00628.1; -; mRNA. DR EMBL; AJ250235; CAB65962.1; -; Genomic_DNA. DR EMBL; BT019958; AAV38761.1; -; mRNA. DR EMBL; AK092416; BAC03882.1; -; mRNA. DR EMBL; AK292937; BAF85626.1; -; mRNA. DR EMBL; CH471096; EAW63046.1; -; Genomic_DNA. DR EMBL; BC039841; AAH39841.2; -; mRNA. DR EMBL; L36178; AAA64787.1; -; Genomic_DNA. DR EMBL; AF495859; AAM18070.1; -; Genomic_DNA. DR CCDS; CCDS11964.1; -. [P22830-1] DR CCDS; CCDS32836.1; -. [P22830-2] DR PIR; A36403; A36403. DR RefSeq; NP_000131.2; NM_000140.3. [P22830-1] DR RefSeq; NP_001012533.1; NM_001012515.2. [P22830-2] DR PDB; 1HRK; X-ray; 2.00 A; A/B=65-423. DR PDB; 2HRC; X-ray; 1.70 A; A/B=65-423. DR PDB; 2HRE; X-ray; 2.50 A; A/B/C/D=65-423. DR PDB; 2PNJ; X-ray; 2.35 A; A/B=65-423. DR PDB; 2PO5; X-ray; 2.20 A; A/B=65-423. DR PDB; 2PO7; X-ray; 2.20 A; A/B=65-423. DR PDB; 2QD1; X-ray; 2.20 A; A/B/C/D=65-423. DR PDB; 2QD2; X-ray; 2.20 A; A/B=65-423. DR PDB; 2QD3; X-ray; 2.20 A; A/B=65-423. DR PDB; 2QD4; X-ray; 2.00 A; A/B=65-423. DR PDB; 2QD5; X-ray; 2.30 A; A/B=65-423. DR PDB; 3AQI; X-ray; 1.70 A; A/B=65-423. DR PDB; 3HCN; X-ray; 1.60 A; A/B=65-423. DR PDB; 3HCO; X-ray; 1.80 A; A/B=65-423. DR PDB; 3HCP; X-ray; 2.00 A; A/B=65-423. DR PDB; 3HCR; X-ray; 2.20 A; A/B=65-423. DR PDB; 3W1W; X-ray; 2.01 A; A/B=61-423. DR PDB; 4F4D; X-ray; 1.80 A; A/B=65-423. DR PDB; 4KLA; X-ray; 2.60 A; A/B=65-423. DR PDB; 4KLC; X-ray; 2.40 A; A/B=65-423. DR PDB; 4KLR; X-ray; 2.18 A; A/B=65-423. DR PDB; 4KMM; X-ray; 2.60 A; A/B=65-423. DR PDB; 4MK4; X-ray; 2.50 A; A/B=65-423. DR PDB; 7CT7; X-ray; 2.00 A; A/B=61-423. DR PDB; 7CTC; X-ray; 2.00 A; A/D=1-423. DR PDBsum; 1HRK; -. DR PDBsum; 2HRC; -. DR PDBsum; 2HRE; -. DR PDBsum; 2PNJ; -. DR PDBsum; 2PO5; -. DR PDBsum; 2PO7; -. DR PDBsum; 2QD1; -. DR PDBsum; 2QD2; -. DR PDBsum; 2QD3; -. DR PDBsum; 2QD4; -. DR PDBsum; 2QD5; -. DR PDBsum; 3AQI; -. DR PDBsum; 3HCN; -. DR PDBsum; 3HCO; -. DR PDBsum; 3HCP; -. DR PDBsum; 3HCR; -. DR PDBsum; 3W1W; -. DR PDBsum; 4F4D; -. DR PDBsum; 4KLA; -. DR PDBsum; 4KLC; -. DR PDBsum; 4KLR; -. DR PDBsum; 4KMM; -. DR PDBsum; 4MK4; -. DR PDBsum; 7CT7; -. DR PDBsum; 7CTC; -. DR AlphaFoldDB; P22830; -. DR SMR; P22830; -. DR BioGRID; 108526; 172. DR DIP; DIP-39632N; -. DR IntAct; P22830; 65. DR MINT; P22830; -. DR STRING; 9606.ENSP00000498358; -. DR BindingDB; P22830; -. DR ChEMBL; CHEMBL3879831; -. DR DrugBank; DB02659; Cholic Acid. DR GlyGen; P22830; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P22830; -. DR PhosphoSitePlus; P22830; -. DR SwissPalm; P22830; -. DR BioMuta; FECH; -. DR DMDM; 85701348; -. DR EPD; P22830; -. DR jPOST; P22830; -. DR MassIVE; P22830; -. DR MaxQB; P22830; -. DR PaxDb; 9606-ENSP00000372326; -. DR PeptideAtlas; P22830; -. DR ProteomicsDB; 54041; -. [P22830-1] DR ProteomicsDB; 54042; -. [P22830-2] DR Pumba; P22830; -. DR Antibodypedia; 9673; 230 antibodies from 29 providers. DR DNASU; 2235; -. DR Ensembl; ENST00000262093.11; ENSP00000262093.6; ENSG00000066926.13. [P22830-1] DR Ensembl; ENST00000652755.1; ENSP00000498358.1; ENSG00000066926.13. [P22830-2] DR GeneID; 2235; -. DR KEGG; hsa:2235; -. DR MANE-Select; ENST00000262093.11; ENSP00000262093.6; NM_000140.5; NP_000131.2. DR UCSC; uc002lgp.5; human. [P22830-1] DR AGR; HGNC:3647; -. DR CTD; 2235; -. DR DisGeNET; 2235; -. DR GeneCards; FECH; -. DR GeneReviews; FECH; -. DR HGNC; HGNC:3647; FECH. DR HPA; ENSG00000066926; Low tissue specificity. DR MalaCards; FECH; -. DR MIM; 177000; phenotype. DR MIM; 612386; gene. DR neXtProt; NX_P22830; -. DR OpenTargets; ENSG00000066926; -. DR Orphanet; 79278; Autosomal erythropoietic protoporphyria. DR PharmGKB; PA28087; -. DR VEuPathDB; HostDB:ENSG00000066926; -. DR eggNOG; KOG1321; Eukaryota. DR GeneTree; ENSGT00390000016258; -. DR InParanoid; P22830; -. DR OMA; DPYHCEC; -. DR OrthoDB; 5970at2759; -. DR PhylomeDB; P22830; -. DR TreeFam; TF300859; -. DR BioCyc; MetaCyc:HS00891-MONOMER; -. DR BRENDA; 4.99.1.1; 2681. DR PathwayCommons; P22830; -. DR Reactome; R-HSA-189451; Heme biosynthesis. DR SABIO-RK; P22830; -. DR SignaLink; P22830; -. DR UniPathway; UPA00252; UER00325. DR BioGRID-ORCS; 2235; 278 hits in 1171 CRISPR screens. DR ChiTaRS; FECH; human. DR EvolutionaryTrace; P22830; -. DR GeneWiki; Ferrochelatase; -. DR GenomeRNAi; 2235; -. DR Pharos; P22830; Tchem. DR PRO; PR:P22830; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; P22830; Protein. DR Bgee; ENSG00000066926; Expressed in trabecular bone tissue and 185 other cell types or tissues. DR ExpressionAtlas; P22830; baseline and differential. DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central. DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; IEA:UniProtKB-KW. DR GO; GO:0004325; F:ferrochelatase activity; IDA:UniProtKB. DR GO; GO:0008198; F:ferrous iron binding; TAS:ProtInc. DR GO; GO:0020037; F:heme binding; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0030350; F:iron-responsive element binding; IEA:Ensembl. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl. DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl. DR GO; GO:0009589; P:detection of UV; IEA:Ensembl. DR GO; GO:0030218; P:erythrocyte differentiation; IEA:Ensembl. DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc. DR GO; GO:0006784; P:heme A biosynthetic process; IEA:Ensembl. DR GO; GO:0006785; P:heme B biosynthetic process; IEA:Ensembl. DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB. DR GO; GO:0048034; P:heme O biosynthetic process; IEA:Ensembl. DR GO; GO:0060586; P:multicellular organismal-level iron ion homeostasis; IEA:Ensembl. DR GO; GO:0046501; P:protoporphyrinogen IX metabolic process; IDA:BHF-UCL. DR GO; GO:0010999; P:regulation of eIF2 alpha phosphorylation by heme; IEA:Ensembl. DR GO; GO:0046984; P:regulation of hemoglobin biosynthetic process; IEA:Ensembl. DR GO; GO:0046685; P:response to arsenic-containing substance; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0017085; P:response to insecticide; IEA:Ensembl. DR GO; GO:0010288; P:response to lead ion; IEA:Ensembl. DR GO; GO:0009416; P:response to light stimulus; TAS:ProtInc. DR GO; GO:0051597; P:response to methylmercury; IEA:Ensembl. DR GO; GO:0070541; P:response to platinum ion; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0034379; P:very-low-density lipoprotein particle assembly; IEA:Ensembl. DR CDD; cd00419; Ferrochelatase_C; 1. DR CDD; cd03411; Ferrochelatase_N; 1. DR Gene3D; 3.40.50.1400; -; 2. DR HAMAP; MF_00323; Ferrochelatase; 1. DR InterPro; IPR001015; Ferrochelatase. DR InterPro; IPR019772; Ferrochelatase_AS. DR InterPro; IPR033644; Ferrochelatase_C. DR InterPro; IPR033659; Ferrochelatase_N. DR NCBIfam; TIGR00109; hemH; 1. DR PANTHER; PTHR11108; FERROCHELATASE; 1. DR PANTHER; PTHR11108:SF1; FERROCHELATASE, MITOCHONDRIAL; 1. DR Pfam; PF00762; Ferrochelatase; 1. DR SUPFAM; SSF53800; Chelatase; 1. DR PROSITE; PS00534; FERROCHELATASE; 1. DR Genevisible; P22830; HS. PE 1: Evidence at protein level; KW 2Fe-2S; 3D-structure; Acetylation; Alternative splicing; Disease variant; KW Heme biosynthesis; Iron; Iron-sulfur; Lyase; Membrane; Metal-binding; KW Mitochondrion; Mitochondrion inner membrane; Porphyrin biosynthesis; KW Reference proteome; Transit peptide. FT TRANSIT 1..54 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 55..423 FT /note="Ferrochelatase, mitochondrial" FT /id="PRO_0000008873" FT ACT_SITE 230 FT ACT_SITE 383 FT BINDING 196 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT BINDING 403 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT BINDING 406 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT BINDING 411 FT /ligand="[2Fe-2S] cluster" FT /ligand_id="ChEBI:CHEBI:190135" FT MOD_RES 57 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P22315" FT MOD_RES 138 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P22315" FT MOD_RES 415 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P22315" FT MOD_RES 415 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P22315" FT VAR_SEQ 64 FT /note="K -> KRYESNI (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_041208" FT VARIANT 55 FT /note="G -> C (in EPP1; dbSNP:rs3848519)" FT /evidence="ECO:0000269|PubMed:1755842" FT /id="VAR_002383" FT VARIANT 62 FT /note="P -> R (in EPP1; dbSNP:rs150830931)" FT /evidence="ECO:0000269|PubMed:12063482" FT /id="VAR_030553" FT VARIANT 71 FT /note="I -> K (in EPP1; enzyme totally inactive)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030554" FT VARIANT 96 FT /note="R -> Q (in dbSNP:rs1041951)" FT /evidence="ECO:0000269|PubMed:2260980, ECO:0000269|Ref.2" FT /id="VAR_012028" FT VARIANT 139 FT /note="Q -> L (in EPP1; enzyme retains 18% of activity; FT dbSNP:rs1356965294)" FT /evidence="ECO:0000269|PubMed:15286165" FT /id="VAR_030555" FT VARIANT 151 FT /note="S -> P (in EPP1; enzyme totally inactive)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030556" FT VARIANT 178 FT /note="E -> K (in EPP1; dbSNP:rs1160565035)" FT /evidence="ECO:0000269|PubMed:12601550" FT /id="VAR_030557" FT VARIANT 182 FT /note="L -> R (in EPP1; enzyme totally inactive)" FT /evidence="ECO:0000269|PubMed:11375302" FT /id="VAR_030558" FT VARIANT 186 FT /note="I -> T (in EPP1; dbSNP:rs1598996367)" FT /evidence="ECO:0000269|PubMed:8757534" FT /id="VAR_002384" FT VARIANT 191 FT /note="Y -> H (in EPP1; enzyme retains 72% of activity; FT dbSNP:rs1055019947)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030559" FT VARIANT 192 FT /note="P -> T (in EPP1; enzyme totally inactive)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030560" FT VARIANT 236 FT /note="C -> Y (in EPP1; enzyme retains 12% of activity; FT dbSNP:rs761962617)" FT /evidence="ECO:0000269|PubMed:15286165" FT /id="VAR_030561" FT VARIANT 260 FT /note="F -> L (in EPP1; enzyme retains 52% of activity)" FT /evidence="ECO:0000269|PubMed:15286165" FT /id="VAR_030562" FT VARIANT 264 FT /note="S -> L (in EPP1)" FT /evidence="ECO:0000269|PubMed:17196862" FT /id="VAR_054629" FT VARIANT 267 FT /note="M -> I (in EPP1; unchanged activity; but increased FT thermolability; dbSNP:rs118204037)" FT /evidence="ECO:0000269|PubMed:1755842" FT /id="VAR_002385" FT VARIANT 283 FT /note="T -> I (in EPP1; enzyme almost inactive)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030563" FT VARIANT 288 FT /note="M -> K (in EPP1; enzyme totally inactive)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030564" FT VARIANT 334 FT /note="P -> L (in EPP1; enzyme retains 19% of activity; FT dbSNP:rs150146721)" FT /evidence="ECO:0000269|PubMed:12601550, FT ECO:0000269|PubMed:9585598" FT /id="VAR_030565" FT VARIANT 362 FT /note="V -> G (in EPP1; dbSNP:rs118204040)" FT /evidence="ECO:0000269|PubMed:7910885" FT /id="VAR_030566" FT VARIANT 379 FT /note="K -> N (in EPP1; enzyme retains 37% of activity)" FT /evidence="ECO:0000269|PubMed:15286165" FT /id="VAR_030567" FT VARIANT 386 FT /note="H -> P (in EPP1; loss of activity)" FT /evidence="ECO:0000269|PubMed:9740232" FT /id="VAR_002386" FT VARIANT 406 FT /note="C -> S (in EPP1; enzyme almost inactive)" FT /evidence="ECO:0000269|PubMed:10942404" FT /id="VAR_030568" FT VARIANT 406 FT /note="C -> Y (in EPP1; enzyme almost inactive; FT dbSNP:rs1324421474)" FT /evidence="ECO:0000269|PubMed:10942404" FT /id="VAR_030569" FT VARIANT 408..411 FT /note="NPVC -> KSVG (in EPP1; no detectable enzymatic FT activity)" FT /evidence="ECO:0000269|PubMed:10942404" FT /id="VAR_030570" FT VARIANT 417 FT /note="F -> S (in EPP1; reduced activity; FT dbSNP:rs118204039)" FT /evidence="ECO:0000269|PubMed:1376018" FT /id="VAR_002387" FT VARIANT 417 FT /note="Missing (in EPP1; enzyme totally inactive)" FT /evidence="ECO:0000269|PubMed:9585598" FT /id="VAR_030571" FT MUTAGEN 110 FT /note="F->A: Increases activity inhibition upon interaction FT with PGRMC1." FT /evidence="ECO:0000269|PubMed:27599036" FT MUTAGEN 196 FT /note="C->S: Loss of activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 360 FT /note="C->S: No loss of activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 395 FT /note="C->S: No loss of activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 403 FT /note="C->D,H: Loss of activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 406 FT /note="C->D,H,S: Loss of activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 411 FT /note="C->H,S: Loss of activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 417 FT /note="F->L: Decreased activity." FT /evidence="ECO:0000269|PubMed:8276824" FT MUTAGEN 417 FT /note="F->Y,W: Greatly reduced activity." FT /evidence="ECO:0000269|PubMed:8276824" FT CONFLICT 228 FT /note="P -> S (in Ref. 4; BAC03882)" FT /evidence="ECO:0000305" FT STRAND 69..75 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 82..84 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 85..93 FT /evidence="ECO:0007829|PDB:3HCN" FT TURN 96..98 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 104..125 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 132..150 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 152..154 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 156..169 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 170..179 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 183..190 FT /evidence="ECO:0007829|PDB:3HCN" FT TURN 196..198 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 199..212 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 218..224 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 231..245 FT /evidence="ECO:0007829|PDB:3HCN" FT TURN 250..252 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 253..255 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 257..263 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 267..270 FT /evidence="ECO:0007829|PDB:3HCN" FT TURN 271..273 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 276..290 FT /evidence="ECO:0007829|PDB:3HCN" FT TURN 291..293 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 297..302 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 306..308 FT /evidence="ECO:0007829|PDB:2HRC" FT STRAND 310..314 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 315..324 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 329..333 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 345..348 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 350..359 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 364..367 FT /evidence="ECO:0007829|PDB:3HCN" FT STRAND 371..373 FT /evidence="ECO:0007829|PDB:4KLR" FT HELIX 375..391 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 397..400 FT /evidence="ECO:0007829|PDB:3HCN" FT HELIX 410..419 FT /evidence="ECO:0007829|PDB:3HCN" SQ SEQUENCE 423 AA; 47862 MW; 3FD50965E8DEABCE CRC64; MRSLGANMAA ALRAAGVLLR DPLASSSWRV CQPWRWKSGA AAAAVTTETA QHAQGAKPQV QPQKRKPKTG ILMLNMGGPE TLGDVHDFLL RLFLDRDLMT LPIQNKLAPF IAKRRTPKIQ EQYRRIGGGS PIKIWTSKQG EGMVKLLDEL SPNTAPHKYY IGFRYVHPLT EEAIEEMERD GLERAIAFTQ YPQYSCSTTG SSLNAIYRYY NQVGRKPTMK WSTIDRWPTH HLLIQCFADH ILKELDHFPL EKRSEVVILF SAHSLPMSVV NRGDPYPQEV SATVQKVMER LEYCNPYRLV WQSKVGPMPW LGPQTDESIK GLCERGRKNI LLVPIAFTSD HIETLYELDI EYSQVLAKEC GVENIRRAES LNGNPLFSKA LADLVHSHIQ SNELCSKQLT LSCPLCVNPV CRETKSFFTS QQL //