Lactate Dehydrogenase: Difference between revisions

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Jasper Small, David Canner, Ann Taylor, Michal Harel, Alexander Berchansky, Joel L. Sussman

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-==Lactate Dehydrogenase==
+<StructureSection load='' size='350' side='right' scene='40/400612/Cv1/1' caption='Lactate dehydrogenase dimer complex with cofactor NAD and pyruvate (PDB code [[4nd4]])'>
-{{STRUCTURE_2a92|  PDB=2a92  | SIZE=400| SCENE= |right|   CAPTION=Lactate dehydrogenase complex with NADH, oxamate and acetate, [[2a92]] }}
+==Function==
+'''L-lactate dehydrogenase''' (L-LDH) catalyzes the interconversion of pyruvate and NADH+ to L-lactate and NAD+.<br />
+'''H-lactate dehydrogenase''' (H-LDH) catalyzes the interconversion of D-lactate and ferricytochrome c to pyruvate and ferrocytochrome c.<br />
+Lactate Dehydrogenase (LDH) is an important enzyme in humans. It occurs in different regions of the body, each region having a unique conformation of different subunits. LDH is a key enzyme in anaerobic respiration. Anaerobic Respiration is the <scene name='Lactate_Dehydrogenase/Cv/4'>conversion of pyruvate into lactate acid</scene> in the absence oxygen. This pathway is important to glycolysis in two main ways. The first is that if pyruvate were to build up glycoysis and thus the generation of ATP would slow. The second is anaerobic respiration allows for the regeneration of NAD+ from NADH. NAD+ is required when glyceraldehyde-3-phosphate dehydrogenase oxidizes glyceraldehyde-3-phosphate in glycolysis, which generates NADH. Lactate dehydrogenase is responsible for the anaerobic conversion of NADH to NAD+. <scene name='40/400612/Cv1/2'>Click here to see the residues which form interactions with pyruvate</scene> in the Lactate Dehydrogenase from ''Cryptosporidium parvum'' ([[4nd4]]).
-<scene name='Jasper_Small_Lactate_Sandbox_1/Basic/1'>Lactate Dehydrogenase (LDH)</scene> is an important enzyme in humans. It occurs in different regions of the body, each region having a unique conformation of different subunits. The Jmole image shown is that of LDH-5, the form found in skeleton muscle and the liver. LDH is a key enzyme in anaerobic respiration. Anaerobic Respiration is the conversion of pyruvate into lactate acid in the absence oxygen. This pathway is important to glycolysis in two main ways. The first is that if pyruvate were to build up glycoysis and thus the generation of ATP would slow. The second is anaerobic respiration allows for the regeneration of NAD+ from NADH. NAD+ is required when glyceraldehyde-3-phosphate dehydrogenase oxidizes glyceraldehyde-3-phosphate in glycolysis, which generates NADH. Lactate dehydrogenase is responsible for the anaerobic conversion of NADH to NAD+.
+See also: [[Cori cycle]], [[Gluconeogenesis]].
+==Human Lactate Dehydrogenase==
-==Structure==
+===Structure===
-LDH is a quaternary protein formed of the combination of two subunits, M and H (Muscle and Heart) into a structure of four of the subunits. The various combinations found in the human body are:
+<scene name='Lactate_Dehydrogenase/Secondary/1'>Human LDH</scene> is a quaternary protein formed of the combination of two subunits, M and H (Muscle and Heart) into a structure of four of the subunits. The various combinations found in the human body are:
 *(4H) Heart
 *(3H1M) Reticuloendothelial
@@ Line 15: / Line 18: @@
 *(4M) Muscle and Liver
-The <scene name='Jasper_Lactate_Final/Secondary/1'>secondary structure</scene> of LDH as shown here is comprised of 40% alpha helices and 23% beta sheets<ref name="2nd">http://www.cheric.org/ippage/e/ipdata/2004/05/file/e200405-701.pdf </ref>. The SCOP data classifies this form of lactate dehydrogenase as mixed beta-alpha-beta, with mainly parallel beta sheets.
+The <scene name='Lactate_Dehydrogenase/Secondary/2'>secondary structure</scene> of LDH as shown here is comprised of 40% alpha helices and 23% beta sheets<ref name="2nd">http://www.cheric.org/ippage/e/ipdata/2004/05/file/e200405-701.pdf </ref>. The SCOP data classifies this form of lactate dehydrogenase as mixed beta-alpha-beta, with mainly parallel beta sheets.
+See also
-==Catalysis==
+*[[Human Lactate Dehydrogenase]]<br />
-Studies have shown that the reaction mechanism of LDH follows an ordered sequence. [[Image:LDH_reaction.jpeg|355px|Catalytic function of LDH (1)]]  In order for lactate to be oxidized NADH must bind to the enzyme first followed by lactate. Several residues are involved in the binding of NADH, including <scene name='Jasper_Lactate_Final/250_final/1'>Lys 250</scene> and <scene name='Jasper_Lactate_Final/85_final/1'>Tyr 85</scene>. Once the NADH is bound to the enzyme, it is then possible for lactate to bind. Lactate binds to the enzyme between the nicotinamide ring and <scene name='Jasper_Lactate_Final/His_195_final/1'>His 195</scene>.  Transfer of a hydride ion then happens quickly in either direction giving a mixture of the two tertiary complexes, enzyme-NAD+-lactate and enzyme-NADH-pyruvate .Finally pyruvate dissociates from the enzyme followed by NAD+<ref name="1st"> http://www.bioc.aecom.yu.edu/labs/calllab/highlights/LDH.htm</ref>.
+*[[Jasper Lactate Final]]<br />
+*[[Rossmann fold]].
+===Catalysis===
+Studies have shown that the reaction mechanism of LDH follows an ordered sequence.
+[[Image:LDH_reaction.jpeg|355px|Catalytic function of LDH (1)]]
+{{Clear}}
+In order for lactate to be oxidized NADH must bind to the enzyme first followed by lactate. <scene name='Lactate_Dehydrogenase/Secondary/5'>Several residues are involved in the binding of NADH</scene>. Once the NADH is bound to the enzyme, it is then possible for lactate to bind (substrate oxamate is shown; the ‑CH3 group is replaced by ‑NH2 to form oxamate). Lactate binds to the enzyme between the nicotinamide ring and several LDH residues.  Transfer of a hydride ion then happens quickly in either direction giving a mixture of the two tertiary complexes, enzyme-NAD+-lactate and enzyme-NADH-pyruvate .Finally pyruvate dissociates from the enzyme followed by NAD+<ref name="1st"> http://www.bioc.aecom.yu.edu/labs/calllab/highlights/LDH.htm</ref>.
 [[Image:2nd.png|355px|(1)]]
-==Kinetics==
+===Kinetics===
 Kinetic studies of lactate dehydrogenase with oxalate and oxamate (structural analogues of lactate and pyruvate)have proven the mechanism stated above. The rate limiting step in this reaction is the rate of dissociation of NAD+ and NADH. The conversion of pyruvate to lactate with the subsequent regeneration of NAD+ is very favorable.
-[[Image:Kin.jpg|600px|(1)]]
+[[Image:Lac.PNG]]
-==Regulation==
+===Regulation===
 As the mechanism is one of equilibrium, There appears to be no regulation specifically designed for lactate dehydrogenase, instead it is dependent on the activation of anaerobic reparation and the presence of pyruvate and NADH, or lactate and NAD+.
 ==3D structures of lactate dehydrogenase==
+[[Lactate dehydrogenase 3D structures]]
-''Updated June 2012''
+</StructureSection>
-[[2e37]], [[2v6m]] – TtL-LDH – ''Thermus thermophilus''<BR />
-[[2xxe]], [[3zzn]], [[4a73]]– TtL-LDH (mutant) <BR />
-[[2x8l]], [[1ceq]] – PfL-LDH – ''Plasmodium falciparum''<BR />
-[[2zqy]], [[2zqz]], [[1llc]] – LcL-LDH – ''Lactobacillus casei''<BR />
-[[3d0o]] - SaL-LDH – ''Staphylococcus aureus''<BR />
-[[2v65]] - L-LDH A chain – ''Champsocephalus gunnari''<BR />
-[[2v6b]] – L-LDH – ''Deinococcus radiodurans''<BR />
-[[2frm]] – CpLDH – ''Cryptosporidium parvum''<BR />
-[[1sov]], [[1pze]] - TgL-LDH – ''Toxoplasma gondii''<BR />
-[[1v6a]] – L-LDH A chain – ''Cyprinus carpio''<BR />
-[[1y6j]] – L-LDH – ''Clostridium thermocellum''<BR />
-[[1ldb]] - GsL-LDH – ''Geobacillus stearothermophilus''<BR />
-[[1ldm]], [[6ldh]], [[8ldh]] – sdM4-LDH – spiny dogfish<BR />
-[[2ldx]] – C4-LDH - mouse<br />
-[[3pqe]] – BsL-LDH (mutant) – ''Bacillus subtilis''
-===L-LDH from yeast (cytochrome b2)===
-[[1kbj]] - LDH FMN-binding domain
-[[1sze]], [[1lco]], [[2oz0]] -  LDH  FMN-binding domain (mutant) <br />
-[[1kbi]] - LDH FMN-binding domain + pyruvate<br />
-[[1szf]], [[1ldc]] - LDH  FMN-binding domain (mutant) + pyruvate<br />
-[[1szg]] - LDH FMN-binding domain + sulfo-FMN<br />
-[[3ks0]] - LDH residues 86-180 + flavocytochrome b2 heme domain + FAB B2B4
-===L-LDH binary complex===
-[[2ydn]] – PfL-LDH + bicine<BR />
-[[1cet]] - PfL-LDH + chloroquine<BR />
-[[1t2c]] - PfL-LDH + NAD<BR />
-[[1ez4]] - L-LDH + NAD – ''Lactobacillus pentosus''<BR />
-[[1lld]], [[2ldb]] - GsL-LDH + NAD<BR />
-[[2a92]] – PvL-LDH + NAD – ''Plasmodium vivax'' <BR />
-[[2a94]], [[2aa3]] - PvL-LDH + NAD-analog<br />
-[[1u4o]], [[1u4s]], [[1u5a]], [[1xiv]] – PfL-LDH + inhibitor<BR />
-[[2xxb]] – TtL-LDH (mutant) + AMP<br />
-[[3pqf]] – BsL-LDH (mutant) + NAD<br />
-[[3vkv]] - LcLDH + fructose-bisphosphate<br />
-[[4aj1]], [[4aj2]], [[4aj4]], [[4aje]], [[4ajh]], [[4aji]], [[4ajj]], [[4ajk]], [[4ajl]], [[4ajn]], [[4ajo]], [[4al4]] – LDH α chain + inhibitor – rat<br />
-[[4ajp]] – hLDH α chain + inhibitor - human
-===L-LDH ternary complex with inhibitor===
-[[1u5c]] - PfL-LDH + inhibitor + NAD<BR />
-[[1t24]], [[1t25]], [[1t26]] - PfL-LDH + azole derivative + NAD<BR />
-[[1t2e]] - PfL-LDH (mutant) + oxamate + NAD<BR />
-[[1ldg]] - PfL-LDH + oxamate + NAD<BR />
-[[2xxj]] – TtL-LDH (mutant) + oxamate + NAD<BR />
-[[2v7p]] - TtL-LDH + oxamate + NAD<BR />
-[[3om9]], [[3czm]] – TgL-LDH + OXQ + NAD<BR />
-[[3h3f]] – L-LDH A chain + oxamate + NAD – rabbit<BR />
-[[2fnz]] - CpLDH + oxamate + NAD<BR />
-[[1t2f]] - hL-LDH B chain + azole derivative + NAD <BR />
-[[1i0z]] - hL-LDH H chain + oxamate + NAD<BR />
-[[1i10]] - hL-LDH M chain + oxamate + NAD<BR />
-[[1oc4]] – L-LDH + oxamate + NAD – ''Plasmodium berghei''<BR />
-[[1a5z]] - L-LDH + oxamate + NAD – ''Thermotoga maritim''a<BR />
-[[1lth]] - L-LDH + oxamate + NAD – ''Bifidobacterium longum''<BR />
-[[1ldn]] - GsL-LDH + oxamate + NAD<BR />
-[[9ldb]], [[9ldt]] - pL-LDH + oxamate + NAD – pig
-===L-LDH ternary complex with reactants===
-[[1sow]], [[1pzh]] - TgL-LDH + oxalate + NAD<BR />
-[[1t2d]] - PfL-LDH + oxalate + NAD<BR />
-[[1pzf]] - TgL-LDH + oxalate + NAD-analog<br />
-[[1pzg]] - TgL-LDH + sulfate + NAD-analog<br />
-[[3h3j]] – SaL-LDH (mutant) + pyruvate + NAD<BR />
-[[3d4p]] - SaL-LDH + pyruvate + NAD<BR />
-[[2fn7]] - CpLDH + lactate + NAD<BR />
-[[2ewd]] - CpLDH + pyruvate + NAD-analog<br />
-[[2fm3]] - CpLDH + pyruvate + NAD<BR />
-[[5ldh]] - pLDH + citrate + NAD-analog<br />
-[[3ldh]] - sdLDH + pyruvate + NAD<BR />
-[[3pqd]] - BsLDH + fructose-bisphosphate + NAD
-===D-LDH===
-[[3kb6]] – D-LDH + lactate + NAD – ''Aquifex aeolicus''<BR />
-[[1j49]] – LdD-LDH + sulfate + NAD – ''Lactobacillus delbrueckii''<BR />
-[[1j4a]] - LdD-LDH + sulfate<BR />
-[[1f0x]] – D-LDH + FAD – ''Escherichia coli''<BR />
-[[2dld]] - D-LDH + oxamate + NAD – ''Lactobacillus helveticus''
-===L-LDH II===
-[[1x0a]], [[1vbi]] – TtL-LDH II
-===L-Lactate/malate dehydrogenase===
-[[1hye]], [[1hyg]] – L-LDH/MDH – ''Methanocaldococcus jannaschi''
 ==Additional Information==
@@ Line 140: / Line 52: @@
 ==Reference==
+*1- http://www.jbc.org/content/243/17/4526.full.pdf+html
-*1- http://www.bioc.aecom.yu.edu/labs/calllab/highlights/LDH.htm
-*2- http://www.cheric.org/ippage/e/ipdata/2004/05/file/e200405-701.pdf
-*3- http://resources.metapress.com/pdf-preview.axd?code=ulnhp23038060m21&size=largest
-*4- http://www.u676.org/Documents/Chretien-ClinChimActa-95.pdf
-*5- http://www.jbc.org/content/243/17/4526.full.pdf+html
 [[Category:Topic Page]]