title: ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.
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.
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI, United States of America.
authors.forename: Alice R
authors.identifier: 0000-0002-8617-3425
authors.initials: AR
authors.lastname: Walker
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI, United States of America.
authors.forename: Pavel
authors.identifier: 0000-0002-7562-5529
authors.initials: P
authors.lastname: Silvestrov
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, United States of America.
authors.forename: Tina A
authors.initials: TA
authors.lastname: Müller
authors.affiliation: Wayne State University Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI, United States of America.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Podolsky
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dyson
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, United States of America.
authors.forename: Robert P
authors.identifier: 0000-0002-3643-2054
authors.initials: RP
authors.lastname: Hausinger
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI, United States of America.
authors.forename: Gerardo Andrés
authors.initials: GA
authors.lastname: Cisneros
mesh_terms: D001741:Black or African American / Q000706:statistics & numerical data; D000071496:AlkB Enzymes / Q000235:genetics*; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics; D004789:Enzyme Activation; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D006801:Humans; D007656:Ketoglutaric Acids / Q000737:chemistry*; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D010100:Oxygen / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011471:Prostatic Neoplasms / Q000208:ethnology* / Q000235:genetics*; D011485:Protein Binding; D012307:Risk Factors; D013379:Substrate Specificity; D014481:United States / Q000453:epidemiology / Q000208:ethnology
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D007656:Ketoglutaric Acids; D024101:Mitochondrial Proteins; C582297:ALKBH7 protein, human; D000071496:AlkB Enzymes; D010100:Oxygen