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@ARTICLE{Myllykoski:633005,
author = {Myllykoski, Matti and Lundekvam, Malin and Osberg, Camilla
and Nilsen, Solveig Siqveland and Arnesen, Thomas},
title = {{T}he molecular basis for acetylhistidine synthesis by
{H}is{AT}/{NAT}16},
journal = {Nature Communications},
volume = {16},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {PUBDB-2025-02331},
pages = {5960},
year = {2025},
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.},
cin = {EMBL-User},
ddc = {500},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3) / NterAct - Discovery and
functional significance of post-translational N-terminal
acetylation (772039) / Q-Room - Q-Room – Quintetto’s
Holographic Telepresence Room (673617) / FS-Proposal:
BAG-20190768 EC (BAG-20190768-EC) / FS-Proposal:
BAG-20211049 EC (BAG-20211049-EC)},
pid = {G:(DE-HGF)POF4-6G3 / G:(EU-Grant)772039 /
G:(EU-Grant)673617 / G:(DE-H253)BAG-20190768-EC /
G:(DE-H253)BAG-20211049-EC},
experiment = {EXP:(DE-H253)P-P11-20150101 / EXP:(DE-H253)P-P14-20150101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40595645},
doi = {10.1038/s41467-025-61145-x},
url = {https://bib-pubdb1.desy.de/record/633005},
}