User:Sachin Sundar/Sandbox 1: Difference between revisions

A study done by Tabernero et al. using lovastatin and P. manovalli HMG-COA reductase helps us understand the mechanism by which lovastatin inhibits the binding of HMG-COA, which is an intermediary substrate in the biosynthetic process of producing cholesterol. There are two classes of HMG-CoA reductase that is mentioned in  this study. The first being Class I, which is the human HMG-CoA reductase, and Class II which is the P. mevalonii HMG-CoA reductase.  The Lovastatin seems to interact with four different sites within the HMG-COA reductase in P. manovalli. In the first site, LOV- 1, the c5-OH group and it does so through interactions with residues Asn-271 (Asn-755 in Class I), Lys-267 (Lys-691 in Class I) and Glu-83 (Glu-559 in Class I). The second site, LOV-2, binds to the C3-OH group through water mediated hydrogen bonds. One bond is formed with Asn-365 (Arg-590 in Class I) and two hydrogen bonds with Asn-216 through the water mediated hydrogen bonds. The third site, LOV-3 interacts with the carboxylate group and creates a hydrogen bond with Arg-261. In the Class I enzyme Lys-735 and Lys-692 form hydrogen bonds and bind in a similar manner to Arg-261 in LOV-3. Two additional hydrogen bonds are formed to the carboxylate group through a water mediated process with Ser-684 in LOV-3 as well in the Class I enzyme. The fourth and final site, LOV-4, interacts with the decalin ring and forms hydrophobic interactions with Ala-368 and Leu-372 found on the hydrophobic region of the alpha helix of the large domain. (Leu-562 and Val-683 are thought to have similar hydrophobic interactions with decalin ring in the Class I enzyme) The remaining three residues that interact within LOV-4 are Ser-85, Ile-86, and Ala-89 which is located in the alpha helix region downstream from the catalytic residue Glu-83. This binding of lovastatin to the active site inhibits binding of substrate, HMG-COA, as well as preventing the closure of the flap domain, that contains the catalytic His-381, which enables the process of reduction from taking place. The misalignment and failure to close the active site inhibits the function of the protein and prevents catalysis. [13]