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. 2021 Jan 15;22(2):846.
doi: 10.3390/ijms22020846.

Substrate Scope for Human Histone Lysine Acetyltransferase KAT8

Giordano Proietti  1   2 , Yali Wang  2   3 , Chiara Punzo  1 , Jasmin Mecinović  1   2
Affiliations

Substrate Scope for Human Histone Lysine Acetyltransferase KAT8

Giordano Proietti et al. Int J Mol Sci. .

Abstract

Biomedically important histone lysine acetyltransferase KAT8 catalyses the acetyl coenzyme A-dependent acetylation of lysine on histone and other proteins. Here, we explore the ability of human KAT8 to catalyse the acetylation of histone H4 peptides possessing lysine and its analogues at position 16 (H4K16). Our synthetic and enzymatic studies on chemically and structurally diverse lysine mimics demonstrate that KAT8 also has a capacity to acetylate selected lysine analogues that possess subtle changes on the side chain and main chain. Overall, this work highlights that KAT8 has a broader substrate scope beyond natural lysine, and contributes to the design of new chemical probes targeting KAT8 and other members of the histone lysine acetyltransferase (KAT) family.

Keywords: acetylation; epigenetics; histone; lysine; posttranslational modifications.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Histone lysine acetylation by histone lysine acetyltransferases (KATs). (b) View of the crystal structure of the tKAT2A-H3K14-CoASH complex (tKAT2A: cyan; CoASH: pink; H3K14: green) (PDB: 1QSN). (c) View of the crystal structure of the KAT8-AcCoA complex (KAT8: gray; AcCoA: pink) (PDB: 2GIV), highlighting the two catalytically relevant residues C316 and E350.
Figure 2
Figure 2
Exploring the substrate specificity for human KAT8 acetyltransferase, rationale and the panel of selected lysine analogues.
Figure 3
Figure 3
MALDI-TOF MS data showing the KAT8 (2 μM)-catalysed acetylation of H4K*16 histone peptides (100 μM) in the presence of AcCoA co-substrate (300 μM) (a–p); Overlaid MS spectra of KAT8-catalysed reactions (red) and no enzyme control reactions (black) that were quenched after being incubated for 3 h at 37 °C.
Figure 4
Figure 4
Michaelis–Menten plots of the KAT8-catalysed acetylation of: (a) H4K16; (b) H4Kaza16; (c) H4KE16, and (d) H4βhK16.
See this image and copyright information in PMC

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