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 <scene name='75/758442/Asn271/3'>Asn-271</scene> (Asn-755 in Class I), <scene name='75/758442/Lys267/2'>Lys-267</scene> (Lys-691 in Class I) and <scene name='75/758442/Glu83/1'>Glu-83</scene> (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 <scene name='75/758442/Asn365/1'>Asn-365</scene>(Arg-590 in Class I) and two hydrogen bonds with <scene name='75/758442/Asn216/1'>Asn-216</scene> 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 <scene name='75/758442/Arg261/1'>Arg-261</scene> 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<scene name='75/758442/Ala368/1'>Ala-368</scene> and <scene name='75/758442/Leu372/1'>Leu-372</scene> 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]

== Health & Disease in Humans ==