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Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the catalytically inactive Glu291Gln mutant, have been determined. These structures suggest that LCAD harbors functions beyond its historically defined role in mitochondrial β-oxidation of long and medium-chain fatty acids. LCAD is a homotetramer containing one FAD per 43 kDa subunit with Glu291 as the catalytic base. The substrate binding cavity of LCAD reveals key differences which makes it specific for longer and branched chain substrates. The presence of Pro132 near the start of the E helix leads to helix unwinding that, together with adjacent smaller residues, permits binding of bulky substrates such as 3α, 7α, l2α-trihydroxy-5β-cholestan-26-oyl-CoA. This structural element is also utilized by ACAD11, a eucaryotic ACAD of unknown function, as well as bacterial ACADs known to metabolize sterol substrates. Sequence comparison suggests that ACAD10, another ACAD of unknown function, may also share this substrate specificity. These results suggest that LCAD, ACAD10, ACAD11 constitute a distinct class of eucaryotic acyl CoA dehydrogenases.

Titel:	Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases.
Autor/in / Beteiligte Person:	Narayanan, B ; Xia, C ; McAndrew, R ; Shen, AL ; Kim, JP
Link:	Zum Volltext
Zeitschrift:	Scientific reports, Jg. 14 (2024-06-05), Heft 1, S. 12976
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2024
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/s41598-024-63027-6
Schlagwort:	Substrate Specificity Humans Crystallography, X-Ray Catalytic Domain Acyl-CoA Dehydrogenases metabolism Acyl-CoA Dehydrogenases genetics Acyl-CoA Dehydrogenases chemistry Protein Conformation Amino Acid Sequence Acyl-CoA Dehydrogenase, Long-Chain metabolism Acyl-CoA Dehydrogenase, Long-Chain genetics Acyl-CoA Dehydrogenase, Long-Chain chemistry Models, Molecular
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Sci Rep] 2024 Jun 05; Vol. 14 (1), pp. 12976. <i>Date of Electronic Publication: </i>2024 Jun 05. MeSH Terms: Acyl-CoA Dehydrogenase, Long-Chain* / metabolism ; Acyl-CoA Dehydrogenase, Long-Chain* / genetics ; Acyl-CoA Dehydrogenase, Long-Chain* / chemistry ; Models, Molecular* ; Substrate Specificity ; Humans ; Crystallography, X-Ray ; Catalytic Domain ; Acyl-CoA Dehydrogenases / metabolism ; Acyl-CoA Dehydrogenases / genetics ; Acyl-CoA Dehydrogenases / chemistry ; Protein Conformation ; Amino Acid Sequence Comments: Update of: Res Sq. 2024 Feb 29:rs.3.rs-3980524. doi: 10.21203/rs.3.rs-3980524/v1. (PMID: 38464032) References: Nat Genet. 2010 Feb;42(2):137-41. (PMID: 20037589) ; Biochemistry. 2013 Apr 30;52(17):2895-904. (PMID: 23560677) ; Hum Mol Genet. 2001 Sep 15;10(19):2069-77. (PMID: 11590124) ; ACS Infect Dis. 2015 Feb 13;1(2):110-125. (PMID: 26161441) ; Cardiovasc Res. 2013 Dec 1;100(3):441-9. (PMID: 24042017) ; J Biol Chem. 2008 Apr 4;283(14):9435-43. (PMID: 18227065) ; Biochemistry. 1994 Apr 12;33(14):4258-64. (PMID: 8155643) ; J Biol Chem. 2004 Jul 30;279(31):32904-12. (PMID: 15159392) ; J Biol Chem. 2015 Sep 25;290(39):23897-904. (PMID: 26240137) ; Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3. (PMID: 15299374) ; Nature. 2010 Mar 4;464(7285):121-5. (PMID: 20203611) ; Lab Invest. 2009 Dec;89(12):1348-54. (PMID: 19736549) ; Cell Metab. 2010 Sep 8;12(3):283-94. (PMID: 20816094) ; J Cancer Prev. 2021 Mar 30;26(1):32-40. (PMID: 33842404) ; Mol Genet Metab. 2011 Apr;102(4):418-29. (PMID: 21237683) ; J Biol Chem. 2002 Apr 5;277(14):12200-7. (PMID: 11812788) ; Nat Commun. 2023 Feb 21;14(1):959. (PMID: 36810848) ; Anal Biochem. 1976 May 7;72:248-54. (PMID: 942051) ; Biochemistry. 1984 Jul 3;23(14):3154-61. (PMID: 6466635) ; Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21. (PMID: 9757107) ; Anal Biochem. 1990 May 1;186(2):280-4. (PMID: 2363500) ; Biochemistry. 1997 Jul 15;36(28):8455-64. (PMID: 9214289) ; Front Physiol. 2020 May 05;11:386. (PMID: 32431623) ; Biochim Biophys Acta. 1998 Jul 31;1393(1):35-40. (PMID: 9714723) ; Methods Enzymol. 1997;276:307-26. (PMID: 27754618) ; Cardiovasc Res. 2022 Dec 29;118(16):3198-3210. (PMID: 35388887) ; FASEB J. 1995 Jun;9(9):718-25. (PMID: 7601336) ; Am J Hum Genet. 2007 Jul;81(1):87-103. (PMID: 17564966) ; Science. 2013 Nov 1;342(6158):1243417. (PMID: 24051248) ; Hum Mol Genet. 2013 Dec 20;22(25):5249-61. (PMID: 23933733) ; Ann Transl Med. 2018 Dec;6(24):473. (PMID: 30740404) ; J Mol Evol. 2009 Aug;69(2):176-93. (PMID: 19639238) ; Hum Mutat. 2013 Mar;34(3):515-24. (PMID: 23281178) ; Biochemistry. 1999 Jan 5;38(1):257-67. (PMID: 9890906) ; Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15592-7. (PMID: 9861014) ; Med Oncol. 2023 Mar 17;40(4):118. (PMID: 36929466) ; Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002) ; Eur J Biochem. 1997 May 1;245(3):600-7. (PMID: 9182995) ; Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7523-7. (PMID: 8356049) ; J Biol Chem. 1956 Apr;219(2):727-33. (PMID: 13319294) ; NPJ Precis Oncol. 2020 Mar 25;4:7. (PMID: 32219176) ; J Biol Chem. 2004 Apr 16;279(16):16526-34. (PMID: 14752098) ; Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17075-80. (PMID: 17940018) ; Biochemistry. 1995 Feb 21;34(7):2163-71. (PMID: 7857927) ; Biochim Biophys Acta. 2009 Aug;1791(8):806-15. (PMID: 19465148) ; Eur J Biochem. 2004 Feb;271(3):483-93. (PMID: 14728675) ; Int J Biol Sci. 2023 Apr 9;19(7):2114-2131. (PMID: 37151879) ; Redox Biol. 2019 Sep;26:101253. (PMID: 31234015) ; Cancers (Basel). 2023 Jun 03;15(11):. (PMID: 37297007) ; Biochemistry. 2020 Mar 17;59(10):1113-1123. (PMID: 32101684) ; J Biol Chem. 2013 Nov 22;288(47):33837-33847. (PMID: 24121500) ; Am J Respir Crit Care Med. 2019 Jun 15;199(12):1517-1536. (PMID: 30554520) ; Mol Genet Metab. 2020 Sep - Oct;131(1-2):83-89. (PMID: 32389575) ; J Biol Chem. 2014 Apr 11;289(15):10668-10679. (PMID: 24591516) Grant Information: R01 GM029076 United States GM NIGMS NIH HHS; R35-ES028377 United States NH NIH HHS; GM29076 United States NH NIH HHS Substance Nomenclature: EC 1.3.8.8 (Acyl-CoA Dehydrogenase, Long-Chain) ; EC 1.3.- (Acyl-CoA Dehydrogenases) Entry Date(s): Date Created: 20240605 Date Completed: 20240605 Latest Revision: 20240617 Update Code: 20240617 PubMed Central ID: PMC11153573

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Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases.