ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28231280.
- Also identified by DOI 10.1371/journal.pcbi.1005345 and PMC identifier 5322872.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7's ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.
Medical subject headings
- AlkB Enzymes
- Ketoglutaric Acids
- Mitochondrial Proteins
- Polymorphism, Single Nucleotide
- Prostatic Neoplasms