Mechanism-Based Inhibition of Histone Deacetylase 6 by a Selenocyanate is Subject to Redox Modulation.

Organoselenocyanates have attracted considerable attention in recent years due to their therapeutic potential and versatility in medicinal chemistry. Here, we report on the mechanism of inhibition by 5-phenylcarbamoylpentyl selenocyanide (SelSA-2), an analogue of the well-characterized histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, a.k.

Structure of Bifunctional Variediene Synthase Yields Unique Insight on Biosynthetic Diterpene Assembly and Cyclization.

An unusual family of bifunctional terpene synthases has been discovered in which both catalytic domains - a prenyltransferase and a cyclase - are connected by a long, flexible linker. These enzymes are unique to fungi and catalyze the first committed steps in the biosynthesis of complex terpenoid natural products: the prenyltransferase assembles 5-carbon precursors to form C geranylgeranyl diphosphate (GGPP), and the cyclase converts GGPP into a polycyclic hydrocarbon product. Weak domain-domain interactions as well as linker flexibility render these enzymes refractory to crystallization and challenge their visualization by cryo-EM.

Structure and Function of Sabinene Synthase, a Monoterpene Cyclase That Generates a Highly Strained [3.1.0] Bicyclic Product.

Sabinene is a plant natural product with a distinctive strained [3.1.0] bicyclic ring system that is used commercially as a spicy and pine-like fragrance with citrus undertones.

Design, Synthesis, and Structural Evaluation of Acetylated Phenylthioketone Inhibitors of HDAC10.

Histone deacetylase 10 (HDAC10) is unique among the greater HDAC family due to its unusually narrow substrate specificity as a polyamine deacetylase, specifically as an -acetylspermidine hydrolase. Polyamines are essential for cell growth and proliferation; consequently, inhibition of polyamine deacetylation represents a possible strategy for cancer chemotherapy. In this work, we have designed six acetylated phenylthioketone inhibitors of HDAC10 containing positively charged - and -substituted amino groups designed to target interactions with E274, the gatekeeper that recognizes the positively charged ammonium group of the substrate -acetylspermidine.