دورية أكاديمية
Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease.
| العنوان: | Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease. |
|---|---|
| المؤلفون: | Taylor JL, Ayres-Galhardo PH, Brown BL |
| المصدر: | Biochemistry [Biochemistry] 2024 Jul 02; Vol. 63 (13), pp. 1636-1646. Date of Electronic Publication: 2024 Jun 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Chemical Society. |
| مواضيع طبية MeSH: | 5-Aminolevulinate Synthetase*/genetics , 5-Aminolevulinate Synthetase*/metabolism , 5-Aminolevulinate Synthetase*/chemistry , 5-Aminolevulinate Synthetase*/deficiency , Anemia, Sideroblastic*/genetics , Anemia, Sideroblastic*/metabolism, Humans ; Genetic Diseases, X-Linked/genetics ; Genetic Diseases, X-Linked/metabolism ; Loss of Function Mutation ; Enzyme Stability ; Heme/metabolism ; Heme/chemistry ; Porphyrias/genetics ; Porphyrias/metabolism ; Models, Molecular ; Mutation ; Protoporphyria, Erythropoietic |
| مستخلص: | The conserved enzyme aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in certain bacteria and eukaryotes by catalyzing the condensation of glycine and succinyl-CoA to yield aminolevulinic acid. In humans, the ALAS isoform responsible for heme production during red blood cell development is the erythroid-specific ALAS2 isoform. Owing to its essential role in erythropoiesis, changes in human ALAS2 (hALAS2) function can lead to two different blood disorders. X-linked sideroblastic anemia results from loss of ALAS2 function, while X-linked protoporphyria results from gain of ALAS2 function. Interestingly, mutations in the ALAS2 C-terminal extension can be implicated in both diseases. Here, we investigate the molecular basis for enzyme dysfunction mediated by two previously reported C-terminal loss-of-function variants, hALAS2 V562A and M567I. We show that the mutations do not result in gross structural perturbations, but the enzyme stability for V562A is decreased. Additionally, we show that enzyme stability moderately increases with the addition of the pyridoxal 5'-phosphate (PLP) cofactor for both variants. The variants display differential binding to PLP and the individual substrates compared to wild-type hALAS2. Although hALAS2 V562A is a more active enzyme in vitro , it is less efficient concerning succinyl-CoA binding. In contrast, the M567I mutation significantly alters the cooperativity of substrate binding. In combination with previously reported cell-based studies, our work reveals the molecular basis by which hALAS2 C-terminal mutations negatively affect ALA production necessary for proper heme biosynthesis. |
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| معلومات مُعتمدة: | DP2 GM146255 United States GM NIGMS NIH HHS; T32 GM008320 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | EC 2.3.1.37 (5-Aminolevulinate Synthetase) EC 2.3.1.37 (ALAS2 protein, human) 42VZT0U6YR (Heme) |
| SCR Disease Name: | X-linked sideroblastic anemia; Protoporphyria, Erythropoietic, X-Linked Dominant |
| تواريخ الأحداث: | Date Created: 20240618 Date Completed: 20240702 Latest Revision: 20240706 |
| رمز التحديث: | 20240706 |
| مُعرف محوري في PubMed: | PMC11223264 |
| DOI: | 10.1021/acs.biochem.4c00066 |
| PMID: | 38888931 |
| قاعدة البيانات: | MEDLINE |
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