Sanbox Reserved 684: Difference between revisions
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=='''Ornithine Transcarbamoylase'''== | <applet load='3grf' size='500' frame='true' align='right' caption='Orthinine Transcarbamoylase' scene='Insert optional scene name here' />=='''Ornithine Transcarbamoylase'''== | ||
===='''Introduction'''==== | ===='''Introduction'''==== | ||
<scene name='Sanbox_Reserved_684/Otc_structure/1'>Orthinine Transcarbamoylase</scene> (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate and ornithine to form citrulline and phosphate. In plants and microbes, OTC is involved in arginine biosynthesis, but in mammals it is located in the mitochondria and is part of the urea cycle. | |||
OTC is often associated with Ornithine transcarbamoylase deficiency (OTCD). OTCD is a common urea cycle disorder, and it is a genetic disorder which results in a mutated and ineffective form of the enzyme OTC. | OTC is often associated with Ornithine transcarbamoylase deficiency (OTCD). OTCD is a common urea cycle disorder, and it is a genetic disorder which results in a mutated and ineffective form of the enzyme OTC. | ||
===='''Structure'''==== | ===='''Structure'''==== | ||
OTC is a trimer. The monomer unit has a CP-binding domain and an amino acid-binding domain. Each of the two discrete substrate-binding domains (SBDs) have an α/β topology with a central β-pleated sheet embedded in flanking α-helices. | OTC is a trimer. The monomer unit has a CP-binding domain and an amino acid-binding domain. Each of the two discrete substrate-binding domains (SBDs) have an α/β topology with a central β-pleated sheet embedded in flanking α-helices. | ||
The <scene name=' | The <scene name='Sanbox_Reserved_684/Active_site_otc/2'>active site</scene> are located at the interface between the protein monomers.<ref>http://en.wikipedia.org/wiki/Ornithine_transcarbamylase</ref>The crystal structure of human ornithine transcarbamylase (OTCase) complexed with carbamoyl phosphate (CP) and L-norvaline (NOR) has been determined to 1.9-A resolution. There are significant differences in the interactions of CP with the protein, compared with the interactions of the CP moiety of the bisubstrate analogue N-(phosphonoacetyl)-L-ornithine (PALO). The carbonyl plane of CP rotates about 60 degrees compared with the equivalent plane in PALO complexed with OTCase. This positions the side chain of NOR optimally to interact with the carbonyl carbon of CP. The mixed-anhydride oxygen of CP, which is analogous to the methylene group in PALO, interacts with the guanidinium group of Arg-92; the primary carbamoyl nitrogen interacts with the main-chain carbonyl oxygens of Cys-303 and Leu-304, the side chain carbonyl oxygen of Gln-171, and the side chain of Arg-330. The residues that interact with NOR are similar to the residues that interact with the ornithine (ORN) moiety of PALO. The side chain of NOR is well defined and close to the side chain of Cys-303 with the side chains of Leu-163, Leu-200, Met-268, and Pro-305 forming a hydrophobic wall. C-delta of NOR is close to the carbonyl oxygen of Leu-304 (3.56 A), S-gamma atom of Cys-303 (4.19 A), and carbonyl carbon of CP (3.28 A). Even though the N-epsilon atom of ornithine is absent in this structure, the side chain of NOR is positioned to enable the N-epsilon of ornithine to donate a hydrogen to the S-gamma atom of Cys-303 along the reaction pathway. Binding of CP and NOR promotes domain closure to the same degree as PALO, and the active site structure of CP-NOR-enzyme complex is similar to that of the PALO-enzyme complex. The structures of the active sites in the complexes of aspartate transcarbamylase (ATCase) with various substrates or inhibitors are similar to this OTCase structure, consistent with their common evolutionary origin.<ref>http://www.proteopedia.org/wiki/index.php/1c9y</ref> | ||