Medicinal Chemistry Student Seminars

Speaker: Faheem

Diehl Lab

Structural Basis of Sirtuin 6-Catalyzed Nucleosome

Deacetylation

(Student Journal Club)

Abstract: Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are

classes of enzymes that are involved in “writing” and “erasing” acetyl marks on

histones, which are crucial processes involved in regulating chromatin

architecture. Sirtuin 6 (Sirt6), belonging to the family of NAD-dependent HDACs,

regulates gene transcription, aging, and DNA damage repair. An existing

hypothesis in the field is that Sirt6 can efficiently deacetylate acetyl groups on

lysine in histone proteins, specifically H3, on chromatin substrates than the free

histone tail peptides. However, the molecular details of how Sirt6 processes

nucleosome substrates are poorly understood. In this paper, Wang et al. report

the structural basis of Sirt6-mediated nucleosome deacetylation. Sirt6 was shown

to deacetylate H3 histone in nucleosome substrates efficiently but not free histone

H3 protein. By semi-synthesizing a nucleosome consisting of methyl thiourea, the

authors capture Sirt6 in a catalytically poised state. Using Cryo-EM, the authors

delineate the interactions between Sirt6 and the nucleosomes, providing insights

into how Sirt6 targets and regulates chromatin.

Reference: Wang, Z. A.; Markert, J. W.; Whedon, S. D.; Yapa Abeywardana, M.;

Lee, K.; Jiang, H.; Suarez, C.; Lin, H.; Farnung, L.; Cole, P. A. Structural Basis of Sirtuin

6-Catalyzed Nucleosome Deacetylation. J Am Chem Soc 2023, 145 (12), 6811–

6822. https://doi.org/10.1021/jacs.2c13512.

Speaker: Erykah Starr

Barrios Lab

Developing a chemical toolkit to investigate histidine

phosphorylation and its importance in human health

(Research in Progress Seminar)

Abstract: My dissertation research is focused on developing a chemical tool-kit to

study histidine phosphorylation in mammalian proteins. My objective is to develop

fluorogenic substrates for histidine phosphatase activity using the unnatural amino

acid FpCAP. These fluorogenic molecules allow for robust enzymatic assays to be

performed. Specifically, FpCAP can be introduced into peptides with standard

solid phase peptide synthesis (SPPS) techniques and used as a direct read-out

(removal of phosphate as an increase in fluorescence) of phosphatase activity

by PHPT1. Additionally, with the growing list of in vivo substrates, peptide mimics of

these substrates with the FpCAP substituted for the phospho-histidine (pHis) in the

specified sequence can be used for fluorogenic activity assays. In addition, by

developing libraries of FpCAP peptides, the substrate amino acid sequence, or

sequence motif needed for PHPT1 phosphatase activity, can be analyzed. This

information will not only provide novel characterization of sequence motifs for

PHPT1 activity in vitro, but it can also provide insights into not yet identified

substrates of these histidine phosphatases.