DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo.
Acyl Coenzyme A
/ genetics
Amino Acid Metabolism, Inborn Errors
/ genetics
Brain Diseases, Metabolic
/ genetics
Cells, Cultured
Glutaryl-CoA Dehydrogenase
/ deficiency
HEK293 Cells
Humans
Ketoglutarate Dehydrogenase Complex
/ genetics
Ketone Oxidoreductases
/ genetics
Substrate Specificity
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
08 05 2020
08 05 2020
Historique:
received:
06
12
2019
revised:
27
02
2020
accepted:
04
03
2020
pubmed:
12
3
2020
medline:
5
8
2021
entrez:
12
3
2020
Statut:
ppublish
Résumé
Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here, we show that loss of DHTKD1 in glutaryl-CoA dehydrogenase-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine and demonstrate that oxoglutarate dehydrogenase (OGDH) is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, dihydrolipoyl succinyltransferase and dihydrolipoamide dehydrogenase to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. In summary, 2-oxoadipic acid is a substrate for DHTKD1, but also for OGDH in a cell model system. The classical 2-oxoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards 2-oxoadipic acid.
Identifiants
pubmed: 32160276
pii: 5803135
doi: 10.1093/hmg/ddaa037
pmc: PMC7206849
doi:
Substances chimiques
Acyl Coenzyme A
0
glutaryl-coenzyme A
3131-84-8
Ketone Oxidoreductases
EC 1.2.-
DHTKD1 protein, human
EC 1.2.4.2
Ketoglutarate Dehydrogenase Complex
EC 1.2.4.2
OGDHL protein, human
EC 1.2.4.2
Glutaryl-CoA Dehydrogenase
EC 1.3.8.6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1168-1179Subventions
Organisme : NICHD NIH HHS
ID : R03 HD092878
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NICHD NIH HHS
ID : R21 HD088775
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001433
Pays : United States
Organisme : NIGMS NIH HHS
ID : R15 GM116077
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Nature. 2016 Jun 15;534(7608):500-5
pubmed: 27309819
Am J Med Genet. 1980;5(1):35-41
pubmed: 6772026
Hum Mol Genet. 2002 Feb 15;11(4):347-57
pubmed: 11854167
Hum Mutat. 1998;12(3):141-4
pubmed: 9711871
PLoS One. 2014 Feb 03;9(2):e87715
pubmed: 24498361
Biochim Biophys Acta. 2015 May;1852(5):768-77
pubmed: 25558815
J Inherit Metab Dis. 2019 Jan;42(1):117-127
pubmed: 30740735
Pediatr Neurol. 2016 Jun;59:6-12
pubmed: 26995068
Orphanet J Rare Dis. 2013 Apr 09;8:57
pubmed: 23570448
Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):121-128
pubmed: 27615426
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
J Inherit Metab Dis. 2019 Jul;42(4):620-628
pubmed: 30767241
Am J Hum Genet. 1983 May;35(3):438-42
pubmed: 6407303
Biochem J. 1989 Feb 1;257(3):625-32
pubmed: 2649080
Mol Biol Cell. 2014 Nov 1;25(21):3342-9
pubmed: 25165143
FEBS Lett. 2010 Jan 4;584(1):181-6
pubmed: 19932104
Mol Genet Metab. 2019 Apr;126(4):388-396
pubmed: 30709776
Cell. 2014 Sep 11;158(6):1415-1430
pubmed: 25215496
J Inherit Metab Dis. 2015 Sep;38(5):873-9
pubmed: 25860818
Brain. 2011 Jan;134(Pt 1):157-70
pubmed: 20923787
Humangenetik. 1974;24(4):265-70
pubmed: 4442872
J Biol Chem. 1990 Jun 5;265(16):8971-4
pubmed: 2188967
Hum Mol Genet. 1995 Mar;4(3):493-5
pubmed: 7795610
Brain. 2009 Jul;132(Pt 7):1764-82
pubmed: 19433437
Am J Hum Genet. 2012 Dec 7;91(6):1082-7
pubmed: 23141293
Proteins. 2008 May 1;71(2):874-90
pubmed: 18004749
Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):932-939
pubmed: 29752936
J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jan 1;944:166-74
pubmed: 24316529
Biochim Biophys Acta Mol Basis Dis. 2017 Sep;1863(9):2220-2228
pubmed: 28545977
Ann N Y Acad Sci. 1999;893:61-78
pubmed: 10672230
Biochemistry (Mosc). 1997 Sep;62(9):1012-20
pubmed: 9527443
FASEB J. 2019 Mar;33(3):4355-4364
pubmed: 30540494
Eur J Biochem. 2000 Jun;267(12):3583-91
pubmed: 10848975
J Inherit Metab Dis. 2014 May;37(3):327-32
pubmed: 24431009
J Biol Chem. 2014 Oct 24;289(43):29859-73
pubmed: 25210035
J Biol Chem. 2005 Jun 10;280(23):21830-6
pubmed: 15840571
Nat Med. 2006 Mar;12(3):307-9
pubmed: 16491085
J Pathol. 2010 Mar;220(4):499-508
pubmed: 20020510
Biochemistry (Mosc). 1997 Sep;62(9):973-82
pubmed: 9527444
Biochemistry (Mosc). 2017 Jun;82(6):723-736
pubmed: 28601082
Free Radic Biol Med. 2018 Feb 1;115:136-145
pubmed: 29191460
FEBS J. 2008 Oct;275(20):4990-5006
pubmed: 18783430
J Biol Chem. 1967 Mar 10;242(5):902-7
pubmed: 6020442
JIMD Rep. 2016;25:15-19
pubmed: 26141459