7r4l
Crystal structure of human mitochondrial NAD kinaseCrystal structure of human mitochondrial NAD kinase
Structural highlights
Disease[NAKD2_HUMAN] Progressive encephalopathy with leukodystrophy due to DECR deficiency. The disease is caused by variants affecting the gene represented in this entry. Function[NAKD2_HUMAN] Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor. Also has weak NADH kinase activity in vitro; however NADH kinase activity is much weaker than the NAD(+) kinase activity and may not be relevant in vivo.[1] Publication Abstract from PubMedNAD(+) kinases (NADKs) are metabolite kinases that phosphorylate NAD(+) molecules to make NADP(+), a limiting substrate for the generation of reducing power NADPH. NADK2 sustains mitochondrial NADPH production that enables proline biosynthesis and antioxidant defense. However, its molecular architecture and mechanistic regulation remain undescribed. Here, we report the crystal structure of human NADK2, revealing a substrate-driven mode of activation. We find that NADK2 presents an unexpected dimeric organization instead of the typical tetrameric assemblage observed for other NADKs. A specific extended segment (aa 325-365) is crucial for NADK2 dimerization and activity. Moreover, we characterize numerous acetylation events, including those on Lys76 and Lys304, which reside near the active site and inhibit NADK2 activity without disrupting dimerization, thereby reducing mitochondrial NADP(H) production, proline synthesis, and cell growth. These findings reveal important molecular insight into the structure and regulation of a vital enzyme in mitochondrial NADPH and proline metabolism. Crystal structure of human NADK2 reveals a dimeric organization and active site occlusion by lysine acetylation.,Mary C, Soflaee MH, Kesavan R, Gelin M, Brown H, Zacharias G, Mathews TP, Lemoff A, Lionne C, Labesse G, Hoxhaj G Mol Cell. 2022 Jul 13. pii: S1097-2765(22)00609-8. doi:, 10.1016/j.molcel.2022.06.026. PMID:35868311[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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