User:Kelly Roark/Sandbox1 - Revision history

Kelly Roark at 01:54, 13 April 2010

Kelly Roark — Tue, 13 Apr 2010 01:54:19 GMT

←Older revision		Revision as of 01:54, 13 April 2010
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	Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.		Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.

-	[[Image:Pyruvate to lactate.jpg]]	+	[[Image:Pyruvate to lactate.jpg]] [[Image:Structure_NADH.png]]

	== Characteristics of LDH ==		== Characteristics of LDH ==

Kelly Roark at 01:47, 13 April 2010

Kelly Roark — Tue, 13 Apr 2010 01:47:15 GMT

←Older revision		Revision as of 01:47, 13 April 2010
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	Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.		Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.

		+	[[Image:Pyruvate to lactate.jpg]]

	== Characteristics of LDH ==		== Characteristics of LDH ==

Kelly Roark at 01:41, 13 April 2010

Kelly Roark — Tue, 13 Apr 2010 01:41:03 GMT

←Older revision		Revision as of 01:41, 13 April 2010
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-	== Lactate Dehydrogenase ==	+	= Lactate Dehydrogenase =


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	== Catalytic Mechanims ==		== Catalytic Mechanims ==

-	=== Lactate to pyruvate: ===	+	==== Lactate to pyruvate: ====

	A hydride ion is transferred directly from the C2 carbon of lactate to C4 carbon of the nicotinamide ring and a proton is transferred from the lactate hydroxyl group to N3 of H193 <ref name="Zhadin"/>. This results in formation of pyruvate and NADH; it also gives H193 a positive formal charge which is <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/12'>stabilized</scene> by Asp166 in the binding pocket <ref name="Adams"/>.		A hydride ion is transferred directly from the C2 carbon of lactate to C4 carbon of the nicotinamide ring and a proton is transferred from the lactate hydroxyl group to N3 of H193 <ref name="Zhadin"/>. This results in formation of pyruvate and NADH; it also gives H193 a positive formal charge which is <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/12'>stabilized</scene> by Asp166 in the binding pocket <ref name="Adams"/>.

-	=== Pyruvate to lactate: ===	+	==== Pyruvate to lactate: ====

	A hydride ion is directly transferred from the pro-R face of NADH to the C2 carbon of pyruvate and a hydrogen from the N3 group of H193 is transferred to the carbonyl oxygen <ref name="Eq"/>. His 193 acts as the catalytic acid and is stabilized by asp 168. This results in the formation of lactate and NAD+; the positive charge on NAD is stabilized by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/13'>Glu 102</scene> <ref name="Adams"/>.		A hydride ion is directly transferred from the pro-R face of NADH to the C2 carbon of pyruvate and a hydrogen from the N3 group of H193 is transferred to the carbonyl oxygen <ref name="Eq"/>. His 193 acts as the catalytic acid and is stabilized by asp 168. This results in the formation of lactate and NAD+; the positive charge on NAD is stabilized by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/13'>Glu 102</scene> <ref name="Adams"/>.

Kelly Roark at 01:39, 13 April 2010

Kelly Roark — Tue, 13 Apr 2010 01:39:26 GMT

←Older revision		Revision as of 01:39, 13 April 2010
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-	Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>~~. The direction of the reaction is determined by the relative concentration of each substrate~~. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.	+	Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.


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	LDH functions as a tetramer ''in vivo'' and is made of two kinds of subunits, H and M, each of which are encoded by a different gene. This results in 5 different isoenzymes (2 homotetramers and 3 heterotetramers) <ref name="Market"/>.		LDH functions as a tetramer ''in vivo'' and is made of two kinds of subunits, H and M, each of which are encoded by a different gene. This results in 5 different isoenzymes (2 homotetramers and 3 heterotetramers) <ref name="Market"/>.
-	Different isoenzymes have different catalytic, physical properties, are regulated differently, and expressed in different kinds of tissues <ref name="McClendon"/>. These differences are due to the different kinetic properties of the different subunits <ref name="Read"/>. The subunits associate randomly; thus, isoenzyme expression in different tissues is determined by the availability of each type of subunit, which in turn is decided by the relative synthesis rates of the subunits and the gene expression for each tissue type(<ref name="Market"/>.	+	Different isoenzymes have different catalytic and physical properties, are regulated differently, and expressed in different kinds of tissues <ref name="McClendon"/>. These differences are due to the different kinetic properties of the different subunits <ref name="Read"/>. The subunits associate randomly; thus, isoenzyme expression in different tissues is determined by the availability of each type of subunit, which in turn is decided by the relative synthesis rates of the subunits and the gene expression for each tissue type <ref name="Market"/>.

-	The M subunit is found predominantly in anaerobic tissues including skeletal muscle and liver <ref name="Read"/>. The H subunit is more commonly found in tissues with a ready source of oxygen and that metabolize lactate including the heart and the brain. In heart muscle, the H4 homotetramer is most commonly found ~~(LDH-1 isoenzyme)~~ but the H3M isoenzyme is also found at a lower level of expression.	+	The M subunit is found predominantly in anaerobic tissues including skeletal muscle and liver <ref name="Read"/>. The H subunit is more commonly found in tissues with a ready source of oxygen and that metabolize lactate including the heart and the brain. In heart muscle, the H4 homotetramer is most commonly found but the H3M isoenzyme is also found at a lower level of expression.

-	~~LDH-1~~ usually functions in the cytoplasm and is not membrane bound like the M subunit isoenzymes may be. Due to high ratio of NAD+: NADH, the H subunit in heart muscle is usually complexed with NAD+ <ref name="McClendon"/>. The H subunit form of LDH usually catalyzes the forward reaction: the oxidation of lactate to pyruvate shown above. This generates NADH which is then further utilized in the cytochrome system to generate more energy (ATP)<ref name="Market"/>. The H subunit is regulated by a negative feedback inhibition loop and is inhibited by millimolar amounts of pyruvate <ref name="Adams">PMID:4146647</ref>. When pyruvate levels reach a threshold level, it binds to and forms a complex with LDH, inactivating it. This decreases the number of available enzymes to catalyze the reaction and stalls the conversion of lactate to pyruvate and also keeps the NAD+:NADH ratio at an optimum level <ref name="Market"/>.	+	The H4 isoenzyme usually functions in the cytoplasm and is not membrane bound like the M subunit isoenzymes may be. Due to the high ratio of NAD+: NADH, the H subunit in heart muscle is usually complexed with NAD+ <ref name="McClendon"/>. The H subunit form of LDH usually catalyzes the forward reaction: the oxidation of lactate to pyruvate shown above. This generates NADH which is then further utilized in the cytochrome system to generate more energy in the form of ATP <ref name="Market"/>. The H subunit is regulated by a negative feedback inhibition loop and is inhibited by millimolar amounts of pyruvate <ref name="Adams">PMID:4146647</ref>. When pyruvate levels reach a threshold level, it binds to and forms a complex with LDH, inactivating it. This decreases the number of available enzymes to catalyze the reaction and stalls the conversion of lactate to pyruvate and also keeps the NAD+:NADH ratio at an optimum level <ref name="Market"/>.


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	{{Template:ColorKey_ConSurf_NoYellow_NoGray}}		{{Template:ColorKey_ConSurf_NoYellow_NoGray}}

-	The substrate is bound deep into the LDH:NADH binary complex (10 A) at the interface between the two domains <ref name="Read"/>. The <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/16'>active site</scene> is located in the binding pocket and contains the catalytically crucial His 193 as well as Asp 168, Arg 171, Thr 246 and Arg 106, all of which ~~contirubte~~ to the catalytic geometry of the active site <ref name="Read"/>. Another important structure is the <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/6'>mobile loop</scene> (residues 95-105) which includes the catalytically important Arg 106 <ref name="McClendon"/>. The mobile loop extends into solution in the apoenzyme (when the cofactor is not bound) and is closed across the substrate binding site. It is open to accept substrate for binding and then closes to sequester the binding pocket from the solvent and to introduce Arg 106 into the active site <ref name="Eq">PMID:17483170</ref>. Arg 106 hydrogen bonds to the carbonyl of the substrate <ref name="Read"/>.	+	The substrate is bound deep into the LDH:NADH binary complex (10 Å) at the interface between the two domains <ref name="Read"/>. The <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/16'>active site</scene> is located in the binding pocket and contains the catalytically crucial His 193 as well as Asp 168, Arg 171, Thr 246 and Arg 106, all of which contribute to the catalytic geometry of the active site <ref name="Read"/>. Another important structure is the <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/6'>mobile loop</scene> (residues 95-105) which includes the catalytically important Arg 106 <ref name="McClendon"/>. The mobile loop extends into solution in the apoenzyme (when the cofactor is not bound) and is closed across the substrate binding site when the cofactor and substrate are bound. It is open to accept substrate for binding and then closes to sequester the binding pocket from the solvent and to introduce Arg 106 into the active site <ref name="Eq">PMID:17483170</ref>. Arg 106 hydrogen bonds to the carbonyl of the substrate <ref name="Read"/>.


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	LDH binds to its NAD+ cofactor to form the binary complex. The adenosine of NAD+ binds in the <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/14'>hydrophobic</scene> crevice and is oriented by a hydrogen bond between N1 and the hydroxyl group of a specific <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/11'>tyrosine</scene> residue <ref name="Adams"/>. The residues are colored according to the follwoing key: {{Template:ColorKey_Hydrophobic}},{{Template:ColorKey_Polar}}. The binary complex is in a range of conformations, some of which are able to bind the substrate (open conformation) and some of which cannot (closed conformation). These forms are in equilibrium; however, the equilibrium lies with the closed conformation <ref name="Zhadin">PMID:18487309</ref>.		LDH binds to its NAD+ cofactor to form the binary complex. The adenosine of NAD+ binds in the <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/14'>hydrophobic</scene> crevice and is oriented by a hydrogen bond between N1 and the hydroxyl group of a specific <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/11'>tyrosine</scene> residue <ref name="Adams"/>. The residues are colored according to the follwoing key: {{Template:ColorKey_Hydrophobic}},{{Template:ColorKey_Polar}}. The binary complex is in a range of conformations, some of which are able to bind the substrate (open conformation) and some of which cannot (closed conformation). These forms are in equilibrium; however, the equilibrium lies with the closed conformation <ref name="Zhadin">PMID:18487309</ref>.

-	Eventually an open binary complex encounters a molecule of substrate. Approximately 15% of the enzyme unfolds around the binding pocket so that it the substrate can reach the active site <ref name="McClendon"/>. The substrate is brought into the binding pocket through a salt bridge that forms between the negatively charged carboxyl group of the substrate and <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/9'>Arg 171</scene> <ref name="McClendon"/>. When the substrate is positioned close to the active site, the mobile loop closes over the active site entrance bringing <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/8'>Arg 106</scene> (a key catalytic residue) deep into the active site pocket and in close contact with the substrate <ref name="Eq"/>. Closure of the loop prevents solvent access to the active site and facilitates hydride transfer. Loop closure also causes the enzyme to tighten around the substrate and NAD+ cofactor, bringing them into the proper geometry for catalysis. Loop closure is facilitated by interactions between ~~R106~~ on the loop and both phosphates of the cofactor <ref name="Adams"/>. Collapse of the loop also helps orient the pro-R hydrogen on the C4 carbon of the nicotinamide ring into close alignment with the proper side of the substrate for hydride transfer <ref name="Zhadin"/>.	+	Eventually an open binary complex encounters a molecule of substrate. Approximately 15% of the enzyme unfolds around the binding pocket so that it the substrate can reach the active site <ref name="McClendon"/>. The substrate is brought into the binding pocket through a salt bridge that forms between the negatively charged carboxyl group of the substrate and <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/9'>Arg 171</scene> <ref name="McClendon"/>. When the substrate is positioned close to the active site, the mobile loop closes over the active site entrance bringing <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/8'>Arg 106</scene> (a key catalytic residue) deep into the active site pocket and in close contact with the substrate <ref name="Eq"/>. Closure of the loop prevents solvent access to the active site and facilitates hydride transfer. Loop closure also causes the enzyme to tighten around the substrate and NAD+ cofactor, bringing them into the proper geometry for catalysis. Loop closure is facilitated by interactions between Arg 106 on the loop and both phosphates of the cofactor <ref name="Adams"/>. Collapse of the loop also helps orient the pro-R hydrogen on the C4 carbon of the nicotinamide ring into close alignment with the proper side of the substrate for hydride transfer <ref name="Zhadin"/>.


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	== Catalytic Mechanims ==		== Catalytic Mechanims ==

-	Lactate to pyruvate:	+	=== Lactate to pyruvate: ===

	A hydride ion is transferred directly from the C2 carbon of lactate to C4 carbon of the nicotinamide ring and a proton is transferred from the lactate hydroxyl group to N3 of H193 <ref name="Zhadin"/>. This results in formation of pyruvate and NADH; it also gives H193 a positive formal charge which is <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/12'>stabilized</scene> by Asp166 in the binding pocket <ref name="Adams"/>.		A hydride ion is transferred directly from the C2 carbon of lactate to C4 carbon of the nicotinamide ring and a proton is transferred from the lactate hydroxyl group to N3 of H193 <ref name="Zhadin"/>. This results in formation of pyruvate and NADH; it also gives H193 a positive formal charge which is <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/12'>stabilized</scene> by Asp166 in the binding pocket <ref name="Adams"/>.

-	Pyruvate to lactate:	+	=== Pyruvate to lactate: ===

	A hydride ion is directly transferred from the pro-R face of NADH to the C2 carbon of pyruvate and a hydrogen from the N3 group of H193 is transferred to the carbonyl oxygen <ref name="Eq"/>. His 193 acts as the catalytic acid and is stabilized by asp 168. This results in the formation of lactate and NAD+; the positive charge on NAD is stabilized by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/13'>Glu 102</scene> <ref name="Adams"/>.		A hydride ion is directly transferred from the pro-R face of NADH to the C2 carbon of pyruvate and a hydrogen from the N3 group of H193 is transferred to the carbonyl oxygen <ref name="Eq"/>. His 193 acts as the catalytic acid and is stabilized by asp 168. This results in the formation of lactate and NAD+; the positive charge on NAD is stabilized by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/13'>Glu 102</scene> <ref name="Adams"/>.

Kelly Roark at 19:33, 8 April 2010

Kelly Roark — Thu, 08 Apr 2010 19:33:57 GMT

←Older revision		Revision as of 19:33, 8 April 2010
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	In some bacteria, LDH is allosterically activated by fructose 1,6-biphosphate (FBP)<ref name="Fusinobu"/>. LDH is non-allosteric in vertebrates.		In some bacteria, LDH is allosterically activated by fructose 1,6-biphosphate (FBP)<ref name="Fusinobu"/>. LDH is non-allosteric in vertebrates.

-	In the tetramer , there are four active sites but only two FBP binding sites. The FBP binding site is at the horizontal plane of symmetry of the tetramer <ref name="~~Fushinobu~~"/>. Arg 173 and His 188 form salt bridges with the phosphates of FBP to bind FBP in the binding pocket. The binding site is adjacent to the active site and His 193. FBP binding neutralizes the positive charge repulsion at the subunit interface and causes a conformational change in the interface and the quaternary structure. The active site is affected by the conformation change and takes on an active conformation. All four active sites are activated at the same time; the allosteric effect is concerted throughout the tetramer <ref name="~~Fushinobu~~"/>.	+	In the tetramer , there are four active sites but only two FBP binding sites. The FBP binding site is at the horizontal plane of symmetry of the tetramer <ref name="Fusinobu"/>. Arg 173 and His 188 form salt bridges with the phosphates of FBP to bind FBP in the binding pocket. The binding site is adjacent to the active site and His 193. FBP binding neutralizes the positive charge repulsion at the subunit interface and causes a conformational change in the interface and the quaternary structure. The active site is affected by the conformation change and takes on an active conformation. All four active sites are activated at the same time; the allosteric effect is concerted throughout the tetramer <ref name="Fusinobu"/>.


	==References==		==References==
	<references />		<references />

Kelly Roark at 19:31, 8 April 2010

Kelly Roark — Thu, 08 Apr 2010 19:31:56 GMT

(Difference between revisions)

Kelly Roark at 19:15, 8 April 2010

Kelly Roark — Thu, 08 Apr 2010 19:15:28 GMT

←Older revision		Revision as of 19:15, 8 April 2010
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-	== References ==	+	==References==
-	<~~ref~~ />	+	<references />

Kelly Roark at 19:12, 8 April 2010

Kelly Roark — Thu, 08 Apr 2010 19:12:58 GMT

←Older revision		Revision as of 19:12, 8 April 2010
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-	Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate (Market ~~1984)~~. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue (Read). The direction of the reaction is determined by the relative concentration of each substrate ~~(Doctors Lounge)~~. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor (McClendon).	+	Lactate dehydrogenase (LDH) is an enzyme that catalyzes the stereospecific interconversion of lactate and pyruvate <ref name="Market">PMID:6383647</ref>. This reaction is known as anaerobic homolactic fermentation and is an important way to regenerate NAD+ to allow glycolysis to continue <ref name="Read">PMID:11276087</ref>. The direction of the reaction is determined by the relative concentration of each substrate. Nicotinamide adenine dinucleotide (NAD+ or NADH) is the cofactor for the reaction aand acts as a hydrogen acceptor or donor <ref name="McClendon">PMID:15980172</ref>.

Kelly Roark at 18:07, 8 April 2010

Kelly Roark — Thu, 08 Apr 2010 18:07:45 GMT

←Older revision		Revision as of 18:07, 8 April 2010
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-	The loop collapse also increases the number of charged and hydrophilic groups which balance the charge on NAD+ (achieved by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/10'>Glu 102</scene>) and on His 193 (achieved by Asp166) after the hydride transfer. Substrate ~~recognitions~~ is provided by Ala 236, Thr 246, Arg 171, Gln 102, and Arg 109. Gln 102 and Arg 109 are both located on the underside of the mobile loop and come into contact with the substrate only after loop closure (Read). The positioning of the substrate in respect to C4 of the nicotinamide ring, H193 and R171 determines the specificity of the enzyme for L-lactate as opposed to D-lactate (Adams). The loop remains closed over the active site until catalysis is complete and then opens to release the product (Shinoda et al).	+	The loop collapse also increases the number of charged and hydrophilic groups which balance the charge on NAD+ (achieved by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/10'>Glu 102</scene>) and on His 193 (achieved by Asp166) after the hydride transfer.
		+	<scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/19'>Substrate recognition</scene> is provided by Ala 236, Thr 246, Arg 171, Gln 102, and Arg 109. Gln 102 and Arg 109 are both located on the underside of the mobile loop and come into contact with the substrate only after loop closure (Read). The positioning of the substrate in respect to C4 of the nicotinamide ring, H193 and R171 determines the specificity of the enzyme for L-lactate as opposed to D-lactate (Adams). The loop remains closed over the active site until catalysis is complete and then opens to release the product (Shinoda et al).

Kelly Roark at 18:02, 8 April 2010

Kelly Roark — Thu, 08 Apr 2010 18:02:18 GMT

←Older revision		Revision as of 18:02, 8 April 2010
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	<applet load='1i0z' size='300' frame='true' align='right' caption='Human heart l-lactate dehydrogenase h chain, ternary complex with nadh and oxamate' />		<applet load='1i0z' size='300' frame='true' align='right' caption='Human heart l-lactate dehydrogenase h chain, ternary complex with nadh and oxamate' />

-	As stated above, LDH is a tetramer and each monomer is folded into two domains that are catalytically independent with little interaction between them (Fushinbu). The ~~coenzyme~~ binding domain consists of a Rossman fold: an open, twisted, six stranded, parallel beta sheet flanked by three alpha helices on each side (Read). The cofactor binds in a groove at one end of the beta sheet. Once the substrate has bound, the cofactor is further positioned by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/3'>interactions</scene> between residue 30 and the adenosine phosphate and residue 247 and the nicotinamide phosphate. The elements in each of these resdiues are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.	+	As stated above, LDH is a tetramer and each monomer is folded into two domains that are catalytically independent with little interaction between them (Fushinbu). The <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/18'>cofactor binding domain</scene> consists of a Rossman fold: an open, twisted, six stranded, parallel beta sheet flanked by three alpha helices on each side (Read). The cofactor binds in a groove at one end of the beta sheet. Once the substrate has bound, the cofactor is further positioned by <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/3'>interactions</scene> between residue 30 and the adenosine phosphate and residue 247 and the nicotinamide phosphate. The elements in each of these resdiues are color coded as follows: {{Template:ColorKey_Element_C}}, {{Template:ColorKey_Element_O}}, {{Template:ColorKey_Element_N}}.

-	The substrate binding domain is adjacent to the nicotinamide group of the cofactor. The binding pocket consists of an overall alpha/beta structure which is highly <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/15'>conserved</scene> and consists of residues 163-247 and 267-331 (Exequiel et al).	+	The <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/17'>substrate binding domain</scene> is adjacent to the nicotinamide group of the cofactor. The binding pocket consists of an overall alpha/beta structure which is highly <scene name='User:Kelly_Roark/Sandbox1/Ldh_h_chain_normal/15'>conserved</scene> and consists of residues 163-247 and 267-331 (Exequiel et al).

	{{Template:ColorKey_ConSurf_NoYellow_NoGray}}		{{Template:ColorKey_ConSurf_NoYellow_NoGray}}