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Contents 1 ALAS2 in erythroid heme biosynthesis disorders 1.1 Physiological function of enzyme ALAS2 1.1.1 ALAS tole in heme biosynthesis 1.2 References

ALAS2 in erythroid heme biosynthesis disorders

Enzyme 5’-aminolevulinic acid synthase (ALAS, EC 2.3.1.37) catalyzes the first step in biosynthesis of heme molecule in α-proteobacteria and mitochondria of nonplant eukaryotes. In vertebrates there are two isoforms of ALAS enzyme. The erythroid-specific ALAS2 located on chromosome X is expressed during erythropoiesis and mediates biosynthesis of heme that carries oxygen in hemoglobin. Different mutations thorough the sequence of the enzyme lead to two ALAS2-associated blood disorders. Namely X-linked sideroblastic anemia (XLSA, MIM 300751) and X-linked protoporphyria (XLP, MIM 300752) caused typically by loss-of function (enzyme deficiency) and gain-of-function (enzyme hyperactivity), respectively.

Physiological function of enzyme ALAS2

In vertebrates, there are two genes encoding ALAS enzymes that belong to α-oxoamine synthase family of pyridoxalphosphate(PLP)-dependent enzymes^[1]. ALAS1 is a house-keeping gene expressed ubiquitously, in contrast ALAS2 (gene location Xp11.21) is specific for erythroid progenitor cells^[2]. Both catalyze initial step in biosynthesis of heme cofactor. While the heme cofactor associated with proteins is essential for several physiological processes, for example transport of oxygen in red blood cells, free heme is toxic and perturbations in its metabolic pathway resulting in accumulation of intermediates lead to various blood diseases^[3][4].

ALAS tole in heme biosynthesis

The initial and final steps of 8-step heme biosynthetic pathway take place in mitochondrial matrix. Since the ALAS mediate first reaction it is rate-limiting enzyme regulating the whole pathway, also known as a gatekeeper ^[5]. It catalyzes PLP-dependent condensation of glycine and succinyl-CoA forming 5-aminolevulinic acid (ALA)^[6]. ALA is then transported to cytoplasm where it undergoes subsequent reactions and eventually moves back to the mitochondria to form heme^[7].

The underlying mechanism of the ALAS enzymatic reaction is induced-fit substrate binding via open-to-close conformational transition. At first, the glycine substrate binds to PLP, an active form of vitamin B6, creating an external aldimine. Following deprotonation of glycine enable nucleophilic attack on the second substrate succinyl-CoA. Consequent condensation and decarboxylation form the ALA product. The product release relies on regeneration of an internal aldimine between PLP and ALAS protein^[8].

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References

1. ↑ Eliot AC, Kirsch JF. Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations. Annu Rev Biochem. 2004;73:383-415. doi: 10.1146/annurev.biochem.73.011303.074021. PMID:15189147 doi:http://dx.doi.org/10.1146/annurev.biochem.73.011303.074021
2. ↑ Bishop DF, Henderson AS, Astrin KH. Human delta-aminolevulinate synthase: assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome. Genomics. 1990 Jun;7(2):207-14. doi: 10.1016/0888-7543(90)90542-3. PMID:2347585 doi:http://dx.doi.org/10.1016/0888-7543(90)90542-3
3. ↑ Dailey HA, Meissner PN. Erythroid heme biosynthesis and its disorders. Cold Spring Harb Perspect Med. 2013 Apr 1;3(4):a011676. doi:, 10.1101/cshperspect.a011676. PMID:23471474 doi:http://dx.doi.org/10.1101/cshperspect.a011676
4. ↑ Chiabrando D, Mercurio S, Tolosano E. Heme and erythropoieis: more than a structural role. Haematologica. 2014 Jun;99(6):973-83. doi: 10.3324/haematol.2013.091991. PMID:24881043 doi:http://dx.doi.org/10.3324/haematol.2013.091991
5. ↑ Hunter GA, Ferreira GC. Molecular enzymology of 5-aminolevulinate synthase, the gatekeeper of heme biosynthesis. Biochim Biophys Acta. 2011 Nov;1814(11):1467-73. doi:, 10.1016/j.bbapap.2010.12.015. Epub 2011 Jan 6. PMID:21215825 doi:http://dx.doi.org/10.1016/j.bbapap.2010.12.015
6. ↑ doi: https://dx.doi.org/10.1016/S0021-9258(19)77371-2
7. ↑ Dailey HA, Meissner PN. Erythroid heme biosynthesis and its disorders. Cold Spring Harb Perspect Med. 2013 Apr 1;3(4):a011676. doi:, 10.1101/cshperspect.a011676. PMID:23471474 doi:http://dx.doi.org/10.1101/cshperspect.a011676
8. ↑ Hunter GA, Zhang J, Ferreira GC. Transient kinetic studies support refinements to the chemical and kinetic mechanisms of aminolevulinate synthase. J Biol Chem. 2007 Aug 10;282(32):23025-35. doi: 10.1074/jbc.M609330200. Epub 2007, May 7. PMID:17485466 doi:http://dx.doi.org/10.1074/jbc.M609330200
9. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
10. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644