Citrate Synthase: Difference between revisions

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==The Structure and Mechanism of Citrate Synthase==
==The Structure and Mechanism of Citrate Synthase==
<Structure load='1cts' size='400' frame='true' align='right' scene='Daniel_Eddelman_Sandbox_2/Open_default/1' caption='Citrate Synthase' />
<Structure load='1cts' size='400' frame='true' align='right' scene='Daniel_Eddelman_Sandbox_2/Cts_open_monomer/2' caption='Citrate Synthase' />
Citrate synthase is an enzyme active in the mitochondria, where it is responsible for catalyzing the first reaction of the citric acid cycle (Krebs Cycle): the condensation of acetyl-CoA and oxaloacetate to form citrate.  Although it is a mitochondrial enzyme (in fact, it is often used as a quantitative enzyme marker for intact mitochondria), it is encoded by nuclear DNA, not mitochondrial <ref>"Citrate Synthase -." Wikipedia, the Free Encyclopedia. Web. 22 Mar. 2010. <http://en.wikipedia.org/wiki/Citrate_synthase></ref>. The standard free energy change (ΔG°’) for the citrate synthase reaction is
Citrate synthase is an enzyme active in the mitochondria, where it is responsible for catalyzing the first reaction of the citric acid cycle (Krebs Cycle): the condensation of acetyl-CoA and oxaloacetate to form citrate.  Although it is a mitochondrial enzyme (in fact, it is often used as a quantitative enzyme marker for intact mitochondria), it is encoded by nuclear DNA, not mitochondrial <ref>"Citrate Synthase -." Wikipedia, the Free Encyclopedia. Web. 22 Mar. 2010. <http://en.wikipedia.org/wiki/Citrate_synthase></ref>. The standard free energy change (ΔG°’) for the citrate synthase reaction is
-31.5kJ/mol <ref name="voet">Voet, Donald, Judith G. Voet, and Charlotte W. Pratt. Fundamentals of Biochemistry: Life at the Molecular Level. Hoboken, NJ: Wiley, 2008.</ref>. This negative free energy value means that citrate synthase is likely to function far from equilibrium under physiological conditions, and is thus a rate-determining enzyme in the citric acid cycle.
-31.5kJ/mol <ref name="voet">Voet, Donald, Judith G. Voet, and Charlotte W. Pratt. Fundamentals of Biochemistry: Life at the Molecular Level. Hoboken, NJ: Wiley, 2008.</ref>. This negative free energy value means that citrate synthase is likely to function far from equilibrium under physiological conditions, and is thus a rate-determining enzyme in the citric acid cycle.
    
    
'''Structure:''' Citrate synthase is a single amino acid chain <scene name='Daniel_Eddelman_Sandbox_2/Cts_open_monomer/1'>monomer</scene>. Biologically, however, it exists as a  
'''Structure:''' Biologically, citrate synthase exists as a  
<scene name='Daniel_Eddelman_Sandbox_2/Cts_open_monomer/2'>homodimer</scene>. Each identical subunit consists of a large and a small domain, and is comprised almost entirely of α helices (making it an all α protein).  In its free enzyme state, citrate synthase exists in “open” form, with its two domains forming a cleft containing the substrate (oxaloacetate) binding site (PDB: [[1cts]]) <ref>PMID:7120407</ref>.  When oxaloacetate binds, the smaller domain undergoes an 18° rotation, sealing the oxaloacetate binding site and resulting in the <scene name='Daniel_Eddelman_Sandbox_2/Closed_homodimer/1'>closed conformation of the homodimer</scene> (PDB: [[2cts]])<ref>PMID:7308213</ref>.  The conformational change is best illustrated via <scene name='User:Wayne_Decatur/1cts_to_2cts_(citrate_synthase)_morph_methods/1ctsto2ctsmorph/5'>a morph between the "open" and "closed" states</scene>. The conformational change not only prevents solvent from reaching the bound substrate, but also generates the acetyl-CoA binding site.  This presence of “open” and “closed” forms results in citrate synthase having Ordered Sequential kinetic behavior <ref name="voet" />.
<scene name='Daniel_Eddelman_Sandbox_2/Cts_open_monomer/2'>homodimer</scene>  of a single amino acid chain <scene name='Daniel_Eddelman_Sandbox_2/Cts_open_monomer/1'>monomer</scene>. Each identical subunit consists of a large and a small domain, and is comprised almost entirely of α helices (making it an all α protein).  In its free enzyme state, citrate synthase exists in “open” form, with its two domains forming a cleft containing the substrate (oxaloacetate) binding site (PDB: [[1cts]]) <ref>PMID:7120407</ref>.  When oxaloacetate binds, the smaller domain undergoes an 18° rotation, sealing the oxaloacetate binding site and resulting in the <scene name='Daniel_Eddelman_Sandbox_2/Closed_homodimer/1'>closed conformation of the homodimer</scene> (PDB: [[2cts]])<ref>PMID:7308213</ref>.  The conformational change is best illustrated via <scene name='User:Wayne_Decatur/1cts_to_2cts_(citrate_synthase)_morph_methods/1ctsto2ctsmorph/5'>a morph between the "open" and "closed" states</scene>. The conformational change not only prevents solvent from reaching the bound substrate, but also generates the acetyl-CoA binding site.  This presence of “open” and “closed” forms results in citrate synthase having Ordered Sequential kinetic behavior <ref name="voet" />.


'''Mechanism:''' The reaction mechanism for citrate synthase was proposed by James Remington.  In this mechanism, three ionizable side chains in the  
'''Mechanism:''' The reaction mechanism for citrate synthase was proposed by James Remington.  In this mechanism, three ionizable side chains in the  
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