Myllykoski Matti, Lundekvam Malin, Osberg Camilla, Nilsen Solveig Siqveland, Arnesen Thomas
Department of Biomedicine, University of Bergen, Bergen, Norway.
Department of Surgery, Haukeland University Hospital, Bergen, Norway.
Nat Commun. 2025 Jul 1;16(1):5960. doi: 10.1038/s41467-025-61145-x.
Acetylhistidine has been detected in human blood, but its origin and function are not known. It is formed when the acetyl group of acetyl-CoA is transferred to the α-amino group of histidine. Here we identify the intracellular NAT16 as the human histidine acetyltransferase (HisAT) responsible for histidine acetylation in vitro and in vivo. A NAT16 variant (p.Phe63Ser) present in over 5% of the population was previously found to correlate with reduced plasma levels of acetylhistidine and increased risk of kidney disease. Our biochemical analysis of HisAT/NAT16 Phe63Ser shows reduced affinity for Histidine supporting a model where this variant has less acetylhistidine catalysis leading to lower blood level of acetylhistidine. We find that HisAT adopts a double-GNAT (Gcn5-related N-Acetyltransferase) fold where the N-terminal domain binds acetyl-CoA and with distinct active site conformation allowing the binding of histidine in between the two domains. We detect similar structures from across living organisms and find that the HisAT structure is conserved in several archaeal and bacterial species. In sum, NAT16 is the human histidine acetyltransferase utilizing a rare double-GNAT structure to steer plasma acetylhistidine levels with potential impact for kidney function.
已在人体血液中检测到乙酰组氨酸，但其来源和功能尚不清楚。它是在乙酰辅酶A的乙酰基转移到组氨酸的α-氨基时形成的。在这里，我们确定细胞内的NAT16为人组氨酸乙酰转移酶（HisAT），它在体外和体内负责组氨酸的乙酰化。先前发现，超过5%的人群中存在的一种NAT16变体（p.Phe63Ser）与血浆中乙酰组氨酸水平降低和肾病风险增加相关。我们对HisAT/NAT16 Phe63Ser的生化分析表明，其对组氨酸的亲和力降低，这支持了一种模型，即这种变体的乙酰组氨酸催化作用较弱，导致血液中乙酰组氨酸水平较低。我们发现HisAT采用双GNAT（与Gcn5相关的N-乙酰转移酶）折叠结构，其中N端结构域结合乙酰辅酶A，且具有独特的活性位点构象，允许组氨酸在两个结构域之间结合。我们在各种生物中检测到类似的结构，并发现HisAT结构在几种古细菌和细菌物种中是保守的。总之，NAT16是人类组氨酸乙酰转移酶，利用罕见的双GNAT结构来调节血浆乙酰组氨酸水平，对肾功能可能产生影响。
