eCommons will be completely unavailable from 8:00am April 4 until 5:00pm April 5, 2018, for software upgrades. Thank you for your patience during this planned service interruption. Please contact us at firstname.lastname@example.org if you have questions or concerns.
Structural Basis For Putrescine Activation, Substrate Specificity And Inhibitor Design Of Human S-Adenosylmethionine Decarboxylase
Structure Based Drug Design is an emerging tool employed in industry as well as academia in the design and discovery of therapeutically relevant molecules. The enzyme S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and an attractive target for design of anti-cancer and anti-proliferative compounds. The polyamines putrescine, spermidine and sperimine are ubiquitous aliphatic cations essential for cell growth, differentiation, and proliferation. The crystal structure of human, potato and bacterial AdoMetDC have been determined previously. The crystal structure of human AdoMetDC with Sadenosylmethionine methyl ester (MeAdoMet) and putrescine bound provided insights into the interactions of the substrate and putrescine with the enzyme. It is well known that putrescine activates the autoprocessing and decarboxylation of human AdoMetDC. To understand the structural basis of the activation, crystal structures of the wild type enzyme and the D174N, E178Q, and E256Q mutants were obtained in the putrescine free form. Putrescine was added to the E178Q and E256Q mutants and the crystal structures obtained. The crystal structures of the putrescine free mutants with MeAdoMet bound were also obtained. A comparison of the crystal structures reveals the details of putrescine activation of Human AdoMetDC. Based on the structural information of the active site and MeAdoMet binding interactions, a series of compounds were synthesized. The crystal structure of human AdoMetDC with a member of each of the series was obtained. The structures coupled to biochemical results and quantum chemical calculations revealed details about the substrate specificity of AdoMetDC. The ligands were bound to AdoMetDC with the adenine base in the higher energy syn conformation. A series of compounds with substitutions at the C8 position of the adenine base were obtained. These compounds turned out to be more potent inhibitors than the unsubstituted parent compounds. The crystal structure of processed form of AdoMetDC from Thermotoga maritima and complexed to MeAdoMet and 5?-Deoxy-5?-dimethyl thioadenosine (MMTA) were also obtained. The conservation of the binding mode of ligands in prokaryotes suggests the extension of inhibitors of human AdoMetDC to other therapeutically relevant species.
Human S-Adenosylmethionine Decarboxylase
dissertation or thesis