The molecular basis for acetylhistidine synthesis by HisAT/NAT16

Area of Science:

• Biochemistry
• Molecular Biology
• Human Physiology

Background:

• Acetylhistidine is present in human blood, but its source and role remain unclear.
• Acetylhistidine is synthesized via the transfer of an acetyl group from acetyl-CoA to histidine.
• A specific NAT16 variant (p.Phe63Ser) is linked to lower acetylhistidine levels and increased kidney disease risk.

Purpose of the Study:

• To identify the enzyme responsible for histidine acetylation in humans.
• To investigate the biochemical basis for the association between the NAT16 variant, acetylhistidine levels, and kidney disease.

Main Methods:

• In vitro and in vivo biochemical assays to characterize enzyme activity.
• Structural analysis of histidine acetyltransferase (HisAT).
• Population genetics analysis of the NAT16 variant.

Main Results:

• The intracellular enzyme NAT16 was identified as the human histidine acetyltransferase (HisAT).
• The NAT16 variant (p.Phe63Ser) exhibits reduced affinity for histidine, leading to decreased acetylhistidine catalysis.
• HisAT possesses a unique double-Gcn5-related N-Acetyltransferase (GNAT) fold, conserved across various organisms.

Conclusions:

• NAT16 is the primary human histidine acetyltransferase, employing a distinctive structural fold.
• The common NAT16 variant impairs acetylhistidine synthesis, potentially influencing plasma levels and kidney health.
• Understanding HisAT's structure and function offers insights into metabolic regulation and disease association.