Small molecule approach to activate human SIRT5

ABSTRACT
The “magnificent seven” human sirtuins play critical roles in various cellular processes including DNA
repair, gene silencing, mitochondrial biogenesis, insulin secretion and apoptosis. They regulate a wide array of
protein and enzyme targets through their NAD+-dependent deacetylase activities. Sirtuins are also thought to
mediate the beneficial effects of low calorie intake to extend longevity in diverse organisms from yeast to
mammals. Small molecules mimicking calorie restriction to stimulate sirtuin activity are attractive therapeutics
against age-related disorders such as cardiovascular diseases, diabetes and neurodegenerative diseases. Little
is known about one of the mitochondrial sirtuins, SIRT5. SIRT5 has emerged as a critical player in maintaining
cardiac health and neuronal viability upon stress, and functions as tumor suppressor in a context specific manner.
Much has been debated about whether SIRT5 has evolved away from being a deacetylase because of its weak
catalytic activity, especially in the in vitro testing. We have, for the first time, identified a SIRT5-selective allosteric
activator, nicotinamide riboside (NR). It can increase SIRT5 deacetylation efficiency with different synthetic
peptide substrates as well as its endogenous cognate substrate. However, the deacylase activity of SIRT5 is
insensitive to NR activation. Mechanism of activation will be further explored in three specific aims. In aim 1, our
effort will be directed at the elucidation of structural determinants required for the differential NR sensitivities and
the identification of allosteric binding site. In aim 2, target engagement and activation of SIRT5 in response to
activator treatment in the cellular context will be investigated. In aim 3, several series of SIRT5 activators will be
synthesized based on our initial screening, structure-activity relationship analysis and docking studies using a
combination of chemical and enzymatic strategies. The knowledge gained in the proposed study will not only
clarify our understanding of the biological functions of SIRT5, but also lead to new therapeutics for metabolic
disorders and age-related diseases.

Grant Number: 5R01GM143176-04
NIH Institute/Center: NIH
Principal Investigator: Yana Cen