# The molecular basis for acetylhistidine synthesis by HisAT/NAT16

## TL;DR

Researchers discovered that the enzyme NAT16 in humans is responsible for creating acetylhistidine, a molecule linked to kidney disease risk.

## Contribution

The study identifies NAT16 as the histidine acetyltransferase (HisAT) and reveals its unique double-GNAT fold structure.

## Key findings

- NAT16 is the enzyme responsible for histidine acetylation in humans.
- The NAT16 Phe63Ser variant has reduced histidine affinity and is linked to lower acetylhistidine levels and kidney disease risk.
- The HisAT structure is conserved in archaeal and bacterial species.

## Abstract

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.

Here, the authors found that human NAT16 acetylates histidine in vitro and in vivo. Biochemical and structural characterisation uncovered a double-GNAT fold with distinct active site architecture that is conserved across species.