TY - JOUR

T1 - Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

AU - Aleshin, Vasily A.

AU - Mkrtchyan, Garik V.

AU - Kaehne, Thilo

AU - Graf, Anastasia V.

AU - Maslova, Maria V.

AU - Bunik, Victoria I.

PY - 2020

Y1 - 2020

N2 - Glutamate dehydrogenase (GDH) is essential for the brain function and highly regulated, according to its role in metabolism of the major excitatory neurotransmitter glutamate. Here we show a diurnal pattern of the GDH acetylation in rat brain, associated with specific regulation of GDH function. Mornings the acetylation levels of K84 (near the ADP site), K187 (near the active site), and K503 (GTP-binding) are highly correlated. Evenings the acetylation levels of K187 and K503 decrease, and the correlations disappear. These daily variations in the acetylation adjust the GDH responses to the enzyme regulators. The adjustment is changed when the acetylation of K187 and K503 shows no diurnal variations, as in the rats after a high dose of thiamine. The regulation of GDH function by acetylation is confirmed in a model system, where incubation of the rat brain GDH with acetyl-CoA changes the enzyme responses to GTP and ADP, decreasing the activity at subsaturating concentrations of substrates. Thus, the GDH acetylation may support cerebral homeostasis, stabilizing the enzyme function during diurnal oscillations of the brain metabolome. Daytime and thiamine interact upon the (de)acetylation of GDH in vitro. Evenings the acetylation of GDH from control animals increases both IC50 GTP and EC50 ADP. Mornings the acetylation of GDH from thiamine-treated animals increases the enzyme IC50 GTP. Molecular mechanisms of the GDH regulation by acetylation of specific residues are proposed. For the first time, diurnal and thiamine-dependent changes in the allosteric regulation of the brain GDH due to the enzyme acetylation are shown. (Figure presented.).

AB - Glutamate dehydrogenase (GDH) is essential for the brain function and highly regulated, according to its role in metabolism of the major excitatory neurotransmitter glutamate. Here we show a diurnal pattern of the GDH acetylation in rat brain, associated with specific regulation of GDH function. Mornings the acetylation levels of K84 (near the ADP site), K187 (near the active site), and K503 (GTP-binding) are highly correlated. Evenings the acetylation levels of K187 and K503 decrease, and the correlations disappear. These daily variations in the acetylation adjust the GDH responses to the enzyme regulators. The adjustment is changed when the acetylation of K187 and K503 shows no diurnal variations, as in the rats after a high dose of thiamine. The regulation of GDH function by acetylation is confirmed in a model system, where incubation of the rat brain GDH with acetyl-CoA changes the enzyme responses to GTP and ADP, decreasing the activity at subsaturating concentrations of substrates. Thus, the GDH acetylation may support cerebral homeostasis, stabilizing the enzyme function during diurnal oscillations of the brain metabolome. Daytime and thiamine interact upon the (de)acetylation of GDH in vitro. Evenings the acetylation of GDH from control animals increases both IC50 GTP and EC50 ADP. Mornings the acetylation of GDH from thiamine-treated animals increases the enzyme IC50 GTP. Molecular mechanisms of the GDH regulation by acetylation of specific residues are proposed. For the first time, diurnal and thiamine-dependent changes in the allosteric regulation of the brain GDH due to the enzyme acetylation are shown. (Figure presented.).

KW - acetylation

KW - cerebral homeostasis

KW - diurnal rhythms

KW - glutamate dehydrogenase

KW - thiamine

U2 - 10.1111/jnc.14951

DO - 10.1111/jnc.14951

M3 - Journal article

C2 - 31886885

AN - SCOPUS:85082095131

VL - 153

SP - 80

EP - 102

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 1

ER -