Abstract
Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that histone deacetylase 10 (HDAC10) is a robust polyamine deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.
Highlights
Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules
A critical strategy for the regulation of polyamine function is reversible acetylation. This strategy is analogous to the regulation of protein function by reversible lysine acetylation through reactions catalysed by histone acetyltransferases and histone deacetylases (HDACs, known more generally as lysine acetyltransferases and lysine deacetylases)
Spermidine is acetylated at the N8 position by an N-acetyltransferase in the cell nucleus[7] and exported to the cytosol, where it is deacetylated by a metaldependent N8-acetylspermidine deacetylase, known as polyamine deacetylase (PDAC)[8,9]
Summary
Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. We recently reported the X-ray crystal structures of both catalytic domains (CDs) of HDAC6, showing that a conserved active site lysine serves as a gatekeeper in CD1, in that it dictates specificity for carboxy-terminal acetyllysine substrates bearing a negatively charged a-carboxylate group[17]. We tested the PDAC activity of hHDAC10 and zHDAC10 against several polyamine substrates using the LC–MS assay (Fig. 2, Supplementary Fig. 3 and Supplementary Table 1).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
