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PMID:19656490

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Citation

Nilsson, R, Schultz, IJ, Pierce, EL, Soltis, KA, Naranuntarat, A, Ward, DM, Baughman, JM, Paradkar, PN, Kingsley, PD, Culotta, VC, Kaplan, J, Palis, J, Paw, BH and Mootha, VK (2009) Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab. 10:119-30

Abstract

Heme biosynthesis consists of a series of eight enzymatic reactions that originate in mitochondria and continue in the cytosol before returning to mitochondria. Although these core enzymes are well studied, additional mitochondrial transporters and regulatory factors are predicted to be required. To discover such unknown components, we utilized a large-scale computational screen to identify mitochondrial proteins whose transcripts consistently coexpress with the core machinery of heme biosynthesis. We identified SLC25A39, SLC22A4, and TMEM14C, which are putative mitochondrial transporters, as well as C1orf69 and ISCA1, which are iron-sulfur cluster proteins. Targeted knockdowns of all five genes in zebrafish resulted in profound anemia without impacting erythroid lineage specification. Moreover, silencing of Slc25a39 in murine erythroleukemia cells impaired iron incorporation into protoporphyrin IX, and vertebrate Slc25a39 complemented an iron homeostasis defect in the orthologous yeast mtm1Delta deletion mutant. Our results advance the molecular understanding of heme biosynthesis and offer promising candidate genes for inherited anemias.

Links

PubMed PMC2745341 Online version:10.1016/j.cmet.2009.06.012

Keywords

Anemia/genetics; Animals; Embryo, Nonmammalian/metabolism; Gene Knockdown Techniques; Heme/biosynthesis; Heme/metabolism; Iron-Sulfur Proteins/genetics; Iron-Sulfur Proteins/metabolism; Mice; Mitochondria/genetics; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins/genetics; Mitochondrial Membrane Transport Proteins/metabolism; Multigene Family; Oligonucleotide Array Sequence Analysis; RNA, Small Interfering/metabolism; Zebrafish/genetics; Zebrafish/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A0R4IMT8

involved_in

GO:0006783: heme biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-091012-5

P

Seeded From UniProt

complete

DANRE:CAF17

involved_in

GO:0006783: heme biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-091012-6

P

Seeded From UniProt

complete

DANRE:TM14C

involved_in

GO:0006783: heme biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-091012-3

P

Seeded From UniProt

complete

DANRE:ISCA1

involved_in

GO:0006783: heme biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-091012-1

P

Seeded From UniProt

complete

DANRE:S2539

involved_in

GO:0006828: manganese ion transport

ECO:0000250: sequence similarity evidence used in manual assertion

RefSeq:NP_011773.1

P

Seeded From UniProt

complete

DANRE:S2539

involved_in

GO:0006783: heme biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-091012-2

P

Seeded From UniProt

complete

DANRE:S2539

enables

GO:0016530: metallochaperone activity

ECO:0000250: sequence similarity evidence used in manual assertion

RefSeq:NP_011773.1

F

Seeded From UniProt

complete

DANRE:S2539

located_in

GO:0005739: mitochondrion

ECO:0000250: sequence similarity evidence used in manual assertion

RefSeq:NP_011773.1

C

Seeded From UniProt

complete


See also

References

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