Histone deacetylase 10 structure and molecular function as a polyamine deacetylase

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Cationic polyamines like spermidine and spermine are essential for cellular functions, regulating biological macromolecules.
• Aberrant polyamine metabolism is linked to cancers, including colon cancer, prostate cancer, and neuroblastoma.
• Intracellular polyamine metabolism is controlled by reversible acetylation.

Purpose of the Study:

• To identify and characterize the enzyme responsible for polyamine deacetylation.
• To elucidate the structural basis for the enzyme's specificity.
• To explore the implications for cancer chemotherapy and autophagy research.

Main Methods:

• Utilized recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish).
• Determined the crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor at 2.85 Å resolution.
• Investigated the enzyme's substrate specificity for N8-acetylspermidine and acetyllysine hydrolysis.

Main Results:

• Identified histone deacetylase 10 (HDAC10) as a potent polyamine deacetylase.
• The crystal structure revealed a glutamate gatekeeper and a constricted active site conferring specificity for N8-acetylspermidine.
• HDAC10 specifically hydrolyzes N8-acetylspermidine and shows reduced activity towards acetyllysine.

Conclusions:

• HDAC10 plays a significant role in regulating polyamine metabolism through deacetylation.
• The structural insights provide a basis for designing specific HDAC10 inhibitors.
• This research lays the groundwork for developing novel cancer therapeutics targeting polyamine metabolism and autophagy.