*100880	Links
ACONITASE, SOLUBLE; ACO1

Alternative titles; symbols

IRON-RESPONSIVE ELEMENT-BINDING PROTEIN 1; IREB1
IRE-BINDING PROTEIN 1; IRP1; IREBP

Gene map locus 9p22-p13

TEXT

Slaughter et al. (1975) reported that an electrophoretic survey had demonstrated 7 alleles at this locus. Among the populations studied, Nigerians showed polymorphism for ACON-S. Aconitase catalyzes the conversion of cis-aconitate to isocitrate. In studies of man-Chinese hamster somatic cell hybrids, Westerveld et al. (1975) showed that human gal-1-p uridyl transferase (GALT; 606999) and aconitase are syntenic.

Povey et al. (1976) assigned the ACO1 gene to chromosome 9. ACO1 and GALT are on 9p in man and on chromosome 4 in the mouse (Nadeau and Eicher, 1982). The location in the mouse was predicted from the human linkage. The smallest region of overlap (SRO) for ACO1 was estimated to be 9p22-p13 (Robson and Meera Khan, 1982).

Aconitase-1 and aconitase-2 (ACO2; 100850) are isozymes present in the cytosol and mitochondria, respectively. Other pairs of cytosolic and mitochondrial isozymes are ALDH1 (100640) and ALDH2 (100650), GOT1 (138180) and GOT2 (138150), IDH1 (147700) and IDH2 (147650), MDH1 (154200) and MDH2 (154100), SOD1 (147450) and SOD2 (147460), and TK1 (188300) and TK2 (188250). In all these cases, the 2 isozymes of different subcellular localization, although similar in structure and function, are encoded by genes on different chromosomes, i.e., are nonsyntenic. The presumption is that in each case both originated from a common ancestral gene in a primordial genome, but that whereas the cytosolic isozyme is encoded by a gene that is a direct descendant from a nuclear progenitor gene, the mitochondrial isozyme, although now encoded by a nuclear gene, is descended from a gene in the bacterium-like progenitor of the mitochondrion. When this primitive organism took up intracellular existence, most of its genes were transferred to the nuclear genome and since they inserted more or less at random into the nuclear genome, it was to be expected that the cytosolic and mitochondrial forms of the enzyme would end up being encoded by genes on different chromosomes. That mitochondrial DNA can be inserted into the nuclear genome is indicated by work such as that of Shay and Werbin (1992) who characterized in detail 2 instances of mitochondrial DNA fragments that had been inserted into the nucleus of HeLa cells. In one of these cases, the mitochondrial sequence encoding cytochrome c oxidase subunit III was contiguous with and 5-prime of exons 2 and 3 of the MYC oncogene (190080) and the chimeric gene was transcribed. Shay and Werbin (1992) discussed possible mechanisms for the transfer of mitochondrial DNA into the nucleus.

Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).

Aconitase-1 is an iron-responsive element (IRE). IREs are translational regulatory sequences in the 5-prime untranslated regions (UTRs) of ferritin mRNA and in the 3-prime UTRs of transferrin receptor mRNA (190010). The cytoplasmic IRE-binding protein interacts with the iron-responsive elements of mRNA. The iron status of the cell determines the ability of the IREBP to bind to an IRE through reversible oxidation-reduction of sulfhydryl groups that are critical for the high affinity RNA/protein interaction. Thus, the IREBP plays a central role in cellular iron homeostasis by regulating ferritin mRNA translation and TFRC mRNA stability. Because of the possibility that idiopathic hemochromatosis, which is the result of a mutant gene that maps to 6p21, is due to mutation in IREBP, Hentze et al. (1989) attempted to map the gene coding for the binding protein. Since the gene had not been cloned, and since they did not have specific antibodies for the protein, they mapped the gene in human/rodent hybrid cells by taking advantage of the different mobilities of the human and rodent IRE/IREBP complexes on nondenaturing polyacrylamide gels. Using a panel of 34 different hybrid cell lines, they assigned the IREBP gene to human chromosome 9. Rouault et al. (1990) used RNA affinity chromatography and 2-dimensional gel electrophoresis to isolate IREBP for protein sequencing. They used an oligonucleotide probe derived from the peptide sequence to isolate a cDNA that encodes a protein of 87 kD. The corresponding mRNA of about 3.6 kb was found in a variety of cell types. Southern hybridization analysis of rodent-human somatic hybrid cell lines corroborated the assignment to chromosome 9. A high frequency RFLP was also identified. By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Irebp gene to mouse chromosome 4.

Eisenstein (2000) reviewed of the role of the iron regulatory proteins, IRP1 and IRP2 (147582), and the molecular control of mammalian iron metabolism. IRP1 is a bifunctional protein with mutually exclusive functions as an IRE RNA-binding protein or as the cytoplasmic isoform of aconitase. Aconitases are iron-sulfur proteins and a 4Fe-4S cluster is required for their enzymatic activity.

Meyron-Holtz et al. (2004) found that IRP2 null cells misregulated iron metabolism when cultured in 3 to 6% oxygen, which is comparable to physiologic tissue concentrations, but not in 21% oxygen, a concentration that activated IRP1 and allowed it to substitute for IRP2. Thus, IRP2 dominates regulation of mammalian iron homeostasis because it alone registers iron concentrations and modulates its RNA-binding activity at physiologic oxygen tensions.

BIOCHEMICAL FEATURES

Crystal Structure

Iron regulatory protein-1 (IRP1) binds IREs in mRNAs, to repress translation or degradation, or binds an iron-sulfur cluster, to become a cytosolic aconitase enzyme. Walden et al. (2006) determined the crystal structure of IRP1 bound to ferritin H (134770) IRE to 2.8-angstrom resolution. The IRP1:ferritin H IRE complex showed an open protein conformation compared with that of cytosolic aconitase. The extended, L-shaped IRP1 molecule embraced the IRE stem loop through interactions at 2 sites separated by about 30 angstroms, each involving about a dozen protein:RNA bonds. Walden et al. (2006) concluded that extensive conformational changes related to binding the IRE or an iron-sulfur cluster explain the alternate functions of IRP1 as an mRNA regulator or enzyme.

SEE ALSO

Azevedo et al. (1979); Mohandas et al. (1979); Robson et al. (1977); Shows and Brown (1977); Teng et al. (1978)

REFERENCES

1. Azevedo, E. S.; Da Silva, M. C. B. O.; Lima, A. M. V.; Fonseca, E. F.; Conseicao, M. M. :

Human aconitase polymorphism in three samples from northeastern Brazil. Ann. Hum. Genet. 43: 7-10, 1979.
PubMed ID : 496396

2. Eisenstein, R. S. :

Iron regulatory proteins and the molecular control of mammalian iron metabolism. Annu. Rev. Nutr. 20: 627-662, 2000.
PubMed ID : 10940348

3. Hentze, M. W.; Seuanez, H. N.; O'Brien, S. J.; Harford, J. B.; Klausner, R. D. :

Chromosomal localization of nucleic acid-binding proteins by affinity mapping: assignment of the IRE-binding protein gene to human chromosome 9. Nucleic Acids Res. 17: 6103-6108, 1989.
PubMed ID : 2771641

4. Meyron-Holtz, E. G.; Ghosh, M. C.; Rouault, T. A. :

Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science 306: 2087-2090, 2004.
PubMed ID : 15604406

5. Mohandas, T.; Sparkes, R. S.; Sparkes, M. C.; Shulkin, J. D.; Toomey, K. E.; Funderburk, S. J. :

Regional localization of human gene loci on chromosome 9: studies of somatic cell hybrids containing human translocations. Am. J. Hum. Genet. 31: 586-600, 1979.
PubMed ID : 292306

6. Nadeau, J. H.; Eicher, E. M. :

Conserved linkage of soluble aconitase and galactose-1-phosphate uridyl transferase in mouse and man: assignment of these genes to mouse chromosome 4. Cytogenet. Cell Genet. 34: 271-281, 1982.
PubMed ID : 6297853

7. Pilz, A.; Woodward, K.; Povey, S.; Abbott, C. :

Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25: 139-149, 1995.
PubMed ID : 7774911

8. Povey, S.; Slaughter, C. A.; Wilson, D. E.; Gormley, I. P.; Buckton, K. E.; Perry, P.; Bobrow, M. :

Evidence for the assignment of the loci AK 1, AK 3 and ACON to chromosome 9 in man. Ann. Hum. Genet. 39: 413-422, 1976.
PubMed ID : 182062

9. Robson, E. B.; Cook, P. J. L.; Buckton, K. E. :

Family studies with the chromosome 9 markers ABO, AK-1, ACON-S and 9qh. Ann. Hum. Genet. 41: 53-60, 1977.
PubMed ID : 200168

10. Robson, E. B.; Meera Khan, P. :

Report of the committee on the genetic constitution of chromosomes 7, 8, and 9. Cytogenet. Cell Genet. 32: 144-152, 1982.
PubMed ID : 7140357

11. Rouault, T. A.; Tang, C. K.; Kaptain, S.; Burgess, W. H.; Haile, D. J.; Samaniego, F.; McBride, O. W.; Harford, J. B.; Klausner, R. D. :

Cloning of the cDNA encoding an RNA regulatory protein: the human iron-responsive element-binding protein. Proc. Nat. Acad. Sci. 87: 7958-7962, 1990.
PubMed ID : 2172968

12. Roychoudhury, A. K.; Nei, M. :

Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.

13. Shay, J. W.; Werbin, H. :

New evidence for the insertion of mitochondrial DNA into the human genome: significance for cancer and aging. Mutat. Res. 275: 227-235, 1992.
PubMed ID : 1383764

14. Shows, T. B.; Brown, J. A. :

Mapping AK-1, ACON-S, and AK-3 to chromosome 9 in man employing an X-9 translocation and somatic cell hybrids. Cytogenet. Cell Genet. 19: 26-37, 1977.
PubMed ID : 196813

15. Slaughter, C. A.; Hopkinson, D. A.; Harris, H. :

Aconitase polymorphism in man. Ann. Hum. Genet. 39: 193-202, 1975.
PubMed ID : 1052766

16. Teng, Y. S.; Tan, S. G.; Lopez, C. G. :

Red cell glyoxalase I and placental soluble aconitase polymorphisms in the three major ethnic groups of Malaysia. Jpn. J. Hum. Genet. 23: 211-215, 1978.

17. Walden, W. E.; Selezneva, A. I.; Dupuy, J.; Volbeda, A.; Fontecilla-Camps, J. C.; Theil, E. C.; Volz, K. :

Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science 314: 1903-1908, 2006.
PubMed ID : 17185597

18. Westerveld, A.; van Henegouwen, B. H. M. A.; Van Someren, H. :

Evidence for synteny between the human loci for galactose-1-phosphate uridyl transferase and aconitase in man-Chinese hamster somatic cell hybrids. Cytogenet. Cell Genet. 14: 453-454, 1975.
PubMed ID : 1192837

CONTRIBUTORS

Ada Hamosh - updated : 2/6/2007
Ada Hamosh - updated : 1/27/2005
Victor A. McKusick - updated : 9/28/2001

CREATION DATE

Victor A. McKusick : 6/4/1986

EDIT HISTORY

alopez : 2/8/2007
terry : 2/6/2007
wwang : 2/3/2005
terry : 1/27/2005
carol : 6/7/2002
carol : 10/3/2001
mcapotos : 9/28/2001
carol : 7/12/2000
mimadm : 2/11/1994
carol : 2/17/1993
carol : 2/2/1993
carol : 8/25/1992
supermim : 3/16/1992
carol : 12/6/1990

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