Inhibition of glutamate dehydrogenase and insulin secretion by KHG26377 does not involve ADP-ribosylation by SIRT4 or deacetylation by SIRT3.
We investigated the mechanisms involved in KHG26377 regulation of glutamate dehydrogenase (GDH) activity, focusing on the roles of SIRT4 and SIRT3. Intraperitoneal injection of mice with KHG26377 reduced GDH activity with concomitant repression of glucose-induced insulin secretion. Consistent with their known functions, SIRT4 ribosylated GDH and reduced its activity, and SIRT3 deacetylated GDH, increasing its activity. However, KHG26377 did not affect SIRT4-mediated ADP-ribosylation/ inhibition or SIRT3-mediated deacetylation/activation of GDH. KHG26377 had no effect on SIRT4 protein levels, and did not alter total GDH, acetylated GDH, or SIRT3 protein levels in pancreatic mitochondrial lysates. These results suggest that the mechanism by which KHG26377 inhibits GDH activity and insulin secretion does not involve ADP-ribosylation of GDH by SIRT4 or deacetylation of GDH by SIRT3.
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
Eun-A
EA
Kim
Seung-Ju
SJ
Yang
Soo Young
SY
Choi
Woo Je
WJ
Lee
Sung-Woo
SW
Cho
D000244:Adenosine Diphosphate / Q000378:metabolism*; D000818:Animals; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
C550808:2-cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride; D007004:Hypoglycemic Agents; D007328:Insulin; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; C525046:Sirt3 protein, mouse; D013844:Thiazoles; D000244:Adenosine Diphosphate; D005969:Glutamate Dehydrogenase; C514813:SIRT4 protein, mouse; D056566:Sirtuin 3; D037761:Sirtuins