Structural Analysis of SMYD3 Lysine Methyltransferase for the Development of Competitive and Specific Enzyme Inhibitors

Dillon K Jarrell; Kelly N Hassell; Ilham Alshiraihi; Debbie C Crans; Mark A Brown

doi:10.3390/diseases10010004

Structural Analysis of SMYD3 Lysine Methyltransferase for the Development of Competitive and Specific Enzyme Inhibitors

Diseases. 2021 Dec 29;10(1):4. doi: 10.3390/diseases10010004.

Authors

Dillon K Jarrell¹, Kelly N Hassell^{2

3}, Ilham Alshiraihi^{4

5}, Debbie C Crans^{2

3}, Mark A Brown^{3

4

6}

Affiliations

¹ Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.
³ Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80523, USA.
⁴ Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
⁵ Biology Department, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁶ Graduate Degree Program in Ecology, Department of Ethnic Studies, Global Health and Health Disparities, Colorado School of Public Health, Colorado State University, Fort Collins, CO 80523, USA.

Abstract

Lysine methylation is among the key posttranslational modifications to histones that contribute to epigenetic regulation. SMYD3 is a lysine methyltransferase that is essential for the proliferation of a range of tumorigenic cells. The findings that SMYD3 is significantly upregulated in most colorectal carcinomas, hepatocellular carcinomas, and breast cell carcinomas support a model in which its aberrant expression modifies established patterns of gene expression, ultimately driving unrestrained proliferation. Herein, we dissect the unique structural features of SMYD3 relative to other SET enzymes, with an emphasis on the implications for selective design of therapeutics for the clinical management of cancer. Further, we illustrate the ability of inhibitors targeting the SET domain of SMYD3 to reduce the viability of colorectal and lung carcinoma cells.

Keywords: Rubisco-LSMT; SET-domain proteins; colorectal; histones; lung carcinoma; small molecule enzyme inhibitors.

Abstract

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