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. |
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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. |
References: | Front Physiol. 2020 Nov 12;11:581386. (PMID: 33281618) Plant Cell. 2003 Sep;15(9):2140-51. (PMID: 12953116) Blood. 2005 May 15;105(10):4103-5. (PMID: 15671438) Blood Cells Mol Dis. 2006 May-Jun;36(3):342-6. (PMID: 16540354) J Bioenerg Biomembr. 1995 Apr;27(2):161-8. (PMID: 7592563) J Biol Chem. 1958 Nov;233(5):1214-9. (PMID: 13598764) Biochem J. 1958 Sep;70(1):71-81. (PMID: 13584304) J Biol Chem. 1989 Mar 5;264(7):4038-44. (PMID: 2917987) Front Physiol. 2021 Jan 21;11:542950. (PMID: 33551825) Blood. 1997 Jan 1;89(1):1-25. (PMID: 8978272) Am J Hum Genet. 2008 Sep;83(3):408-14. (PMID: 18760763) Blood. 1994 Dec 1;84(11):3915-24. (PMID: 7949148) Cell. 2015 May 7;161(4):858-67. (PMID: 25957689) Biochem Soc Trans. 1994 May;22(2):446-50. (PMID: 7958343) Angew Chem Int Ed Engl. 2015 Feb 2;54(6):1851-4. (PMID: 25537779) Mol Cell Biol. 2019 Mar 19;39(7):. (PMID: 30670569) Front Mol Biosci. 2022 Jul 14;9:920668. (PMID: 35911972) Genomics. 1990 Jun;7(2):207-14. (PMID: 2347585) Br J Haematol. 1965 Jan;11:41-8. (PMID: 14247472) J Biol Chem. 1985 Sep 5;260(19):10800-5. (PMID: 4030772) Blood. 2018 Sep 6;132(10):987-998. (PMID: 29991557) Proc Natl Acad Sci U S A. 2022 Oct 11;119(41):e2203628119. (PMID: 36201541) Nat Methods. 2022 Jun;19(6):679-682. (PMID: 35637307) Blood. 2006 Dec 1;108(12):3730-5. (PMID: 16882706) Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1368-73. (PMID: 25605889) Biochemistry. 2015 Sep 15;54(36):5617-31. (PMID: 26300302) J Biol Chem. 2016 Sep 23;291(39):20516-29. (PMID: 27496948) Nat Commun. 2020 Jun 4;11(1):2813. (PMID: 32499479) EMBO J. 2005 Sep 21;24(18):3166-77. (PMID: 16121195) J Biol Chem. 2012 Oct 19;287(43):36201-7. (PMID: 22955281) Pediatr Hematol Oncol. 1994 Jan-Feb;11(1):99-104. (PMID: 8155505) Biochim Biophys Acta. 2011 Nov;1814(11):1467-73. (PMID: 21215825) Biochim Biophys Acta. 1973 Aug 17;320(1):143-56. (PMID: 4748359) Haematologica. 2014 Jun;99(6):973-83. (PMID: 24881043) J Biol Chem. 2022 Mar;298(3):101643. (PMID: 35093382) Biochem J. 1958 Sep;70(1):4-14. (PMID: 13584293) N Engl J Med. 1975 Jan 23;292(4):185-93. (PMID: 1088923) Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2402-7. (PMID: 15701694) PLoS One. 2015 Aug 19;10(8):e0135896. (PMID: 26287972) Mol Genet Metab. 2019 Nov;128(3):164-177. (PMID: 31326287) Science. 2023 Sep 22;381(6664):eadg7492. (PMID: 37733863) Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844) Biochemistry. 1997 Nov 25;36(47):14271-6. (PMID: 9400365) Sci Rep. 2022 May 30;12(1):9024. (PMID: 35637209) Biochim Biophys Acta. 1982 May 7;687(2):204-10. (PMID: 6284220) Mol Genet Metab. 2019 Nov;128(3):298-303. (PMID: 30704898) Annu Rev Biochem. 1967;36:185-210. (PMID: 18257720) J Clin Invest. 2000 Mar;105(6):757-64. (PMID: 10727444) Hum Genet. 2020 Oct;139(10):1197-1207. (PMID: 32596782) Br J Haematol. 2016 Feb;172(4):512-23. (PMID: 26491866) Mol Genet Metab. 2019 Nov;128(3):198-203. (PMID: 30709775) J Biol Chem. 2012 Aug 17;287(34):28943-55. (PMID: 22740690) Protein Sci. 1993 Nov;2(11):1959-65. (PMID: 8268805) Science. 1993 Jan 22;259(5094):522-5. (PMID: 8424176) Cytogenet Cell Genet. 1995;69(3-4):207-8. (PMID: 7698013) Nucleic Acids Res. 1990 Dec 11;18(23):7187-8. (PMID: 2263504) Blood. 1995 Aug 1;86(3):940-8. (PMID: 7620186) Diabetes Care. 2016 May;39(5):833-46. (PMID: 27208380) Plant Cell. 2007 Nov;19(11):3723-38. (PMID: 17981998) Biol Chem. 2022 Aug 29;403(11-12):985-1003. (PMID: 36029525) Exp Hematol. 2012 Jun;40(6):477-86.e1. (PMID: 22269113) J Biol Chem. 2015 Mar 13;290(11):6705-13. (PMID: 25605736) Hum Genet. 1995 Apr;95(4):424-8. (PMID: 7705839) Science. 2016 Feb 12;351(6274):733-7. (PMID: 26912862) J Biochem. 1993 Jul;114(1):103-11. (PMID: 8407861) FEBS Lett. 2021 Dec;595(24):3019-3029. (PMID: 34704252) Science. 2020 Apr 17;368(6488):283-290. (PMID: 32299949) Hum Mutat. 2011 Jun;32(6):590-7. (PMID: 21309041) ACS Chem Biol. 2016 Oct 21;11(10):2847-2853. (PMID: 27556423) J Biol Chem. 2011 Jul 29;286(30):26424-30. (PMID: 21659532) Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1217-28. (PMID: 16962558) BMJ. 1990 Aug 18-25;301(6748):350-1. (PMID: 2205315) Hum Mol Genet. 2013 Apr 1;22(7):1280-8. (PMID: 23263862) Methods Enzymol. 1997;281:309-16. (PMID: 9250995) Blood. 2002 Dec 1;100(12):4236-8. (PMID: 12393718) Nature. 2023 Feb;614(7946):153-159. (PMID: 36697829) Nat Commun. 2017 May 16;8:15212. (PMID: 28508886) Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10775-82. (PMID: 20495089) |
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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