HEMH_HUMAN
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 03-AUG-2022, entry version 221.
DE RecName: Full=Ferrochelatase, mitochondrial;
DE EC=4.99.1.1 {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-LYS-SER--GLY-411, AND
RP CHARACTERIZATION OF VARIANTS EPP1 SER-406; TYR-406 AND
RP 408-LYS-SER--GLY-411.
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=4.99.1.1;
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; 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";
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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; 158.
DR DIP; DIP-39632N; -.
DR IntAct; P22830; 62.
DR MINT; P22830; -.
DR STRING; 9606.ENSP00000372326; -.
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 BioMuta; FECH; -.
DR DMDM; 85701348; -.
DR EPD; P22830; -.
DR jPOST; P22830; -.
DR MassIVE; P22830; -.
DR MaxQB; P22830; -.
DR PaxDb; P22830; -.
DR PeptideAtlas; P22830; -.
DR PRIDE; P22830; -.
DR ProteomicsDB; 54041; -. [P22830-1]
DR ProteomicsDB; 54042; -. [P22830-2]
DR Antibodypedia; 9673; 200 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 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; LGDPYHC; -.
DR PhylomeDB; P22830; -.
DR TreeFam; TF300859; -.
DR BioCyc; MetaCyc:HS00891-MON; -.
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; 265 hits in 1090 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 184 other tissues.
DR ExpressionAtlas; P22830; baseline and differential.
DR Genevisible; P22830; HS.
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:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc.
DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB.
DR GO; GO:0046501; P:protoporphyrinogen IX metabolic process; IDA:BHF-UCL.
DR GO; GO:0009416; P:response to light stimulus; TAS:ProtInc.
DR CDD; cd00419; Ferrochelatase_C; 1.
DR CDD; cd03411; Ferrochelatase_N; 1.
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 PANTHER; PTHR11108; PTHR11108; 1.
DR Pfam; PF00762; Ferrochelatase; 1.
DR TIGRFAMs; TIGR00109; hemH; 1.
DR PROSITE; PS00534; FERROCHELATASE; 1.
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 /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
