ThefunctionofcytochromesP450canbeclassifiedintotwomajordivisions,thosethatoperateinxenobiotic degradationandthosethatplaycriticalrolesinsteroidhormonesynthesis.Duetothecriticalroleof cytochromeP450inhumanhealth,theseenzymesystemshaveoccupiedNIHsupportedinvestigatorsfor manydecades.Thegenerallongtermgoalsoftheresearchprogramaretogainamolecularlevelinsightinto theimpressiverangeoffunctionaldiversitydisplayedbytheseenzymes.Theessentialfocusofthework proposeddealswithtwoimportanthumanenzymesinvolvedinsteroidbiosynthesis,CYP17andCYP51,both currentdrugtargetsforvariousdiseases,includingatherosclerosisandprostatecancer,progressinthis endeavorultimatelydependsongainingadeeperunderstandingoftheirstructureandprecisereaction pathways.Inordertofullyunderstandthepertinentrelationshipofstructuretofunction,itisimportantto acquirestructuralinformationfornotonlythestableterminalstatesinareaction,butalsoforthereaction intermediates,investigationofthelatterhavingbeenhistoricallyimpeded,owingtotheirfleetingexistence. Also,thefactthatthesearemembrane?boundproteinshascomplicatedtheirinvestigationowingtoproblems associatedwithaggregation.Inordertoaddresstheseobstacles,thisresearchprogramemploysanapproach usinginnovativenanodisctechnologywhichnotonlyprovidesanenvironmentmimickingthenaturalcell membranefortheisolatedCYPenzyme,butalsoenablesthesynthesisofuniquefunctionaldyadsoftheCYP withitsnaturaloralternativereductases.Alsoofimmenseimportance,apowerfulcombinationofresonance Ramanspectroscopywiththecryoradiolysistechniquepermitstrappinganddetailedstructural characterizationofotherwiseelusive,butcrucialreactionintermediates,therebyprovidingaheretofore unattainablelevelofinsightintothestructureandfunctionoftheseenzymes.
ThecytochromesP450playcentralrolesinhumanhealth,oneoftheirfunctionsbeingthebiosynthesisof steroidhormones.Theessentialgoalofthisprojectistogainabetterunderstandingofthestructureand functionoftwohumancytochromeP450drugtargets,CYP17A1andCYP51A1.
| Mak, Piotr J; Duggal, Ruchia; Denisov, Ilia G et al. (2018) Human Cytochrome CYP17A1: The Structural Basis for Compromised Lyase Activity with 17-Hydroxyprogesterone. J Am Chem Soc 140:7324-7331 |
