Lactate Dehydrogenase

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 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+. in the Lactate Dehydrogenase from Cryptosporidium parvum (2fm3).

Human Lactate Dehydrogenase

Structure

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
(2H2M) Lungs
(1H3M) Kidneys
(4M) Muscle and Liver

The of LDH as shown here is comprised of 40% alpha helices and 23% beta sheets^[1]. The SCOP data classifies this form of lactate dehydrogenase as mixed beta-alpha-beta, with mainly parallel beta sheets.

Catalysis

Studies have shown that the reaction mechanism of LDH follows an ordered sequence.

In order for lactate to be oxidized NADH must bind to the enzyme first followed by lactate. . 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+^[2].

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.

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+.

Lactate dehydrogenase dimer complex with cofactor NAD and pyruvate (PDB code 2fm3)

Drag the structure with the mouse to rotate

3D structures of lactate dehydrogenase3D structures of lactate dehydrogenase

Updated on 19-August-2014

L-LDHL-LDH

2e37, 2v6m – TtL-LDH – Thermus thermophilus
2xxe, 3zzn, 4a73– TtL-LDH (mutant)
2x8l, 1ceq – PfL-LDH – Plasmodium falciparum
2zqy, 2zqz, 1llc – LcL-LDH – Lactobacillus casei
3vku - LcL-LDH (mutant)
3d0o - SaL-LDH – Staphylococcus aureus
2v65 - L-LDH A chain – Champsocephalus gunnari
2v6b – L-LDH – Deinococcus radiodurans
2frm – CpLDH – Cryptosporidium parvum
1sov, 1pze - TgL-LDH – Toxoplasma gondii
1v6a – L-LDH A chain – Cyprinus carpio
1y6j – L-LDH – Clostridium thermocellum
1ldb - GsL-LDH – Geobacillus stearothermophilus
1ldm, 6ldh, 8ldh – sdM4-LDH – spiny dogfish
2ldx – C4-LDH - mouse
4m1q - BseL-LDH – Bacillus selenitireducens
3pqe – BsL-LDH (mutant) – Bacillus subtilis
4lmr, 4ln1 - LDH – Bacillus cereus
3vpg – TcLDH – Thermus caldophilus

L-LDH from yeast (cytochrome b2)L-LDH from yeast (cytochrome b2)

1kbj - LDH FMN-binding domain
1sze, 1lco, 2oz0 - LDH FMN-binding domain (mutant)
1kbi - LDH FMN-binding domain + pyruvate
1szf, 1ldc - LDH FMN-binding domain (mutant) + pyruvate
1szg - LDH FMN-binding domain + sulfo-FMN
3ks0 - LDH residues 86-180 + flavocytochrome b2 heme domain + FAB B2B4

L-LDH binary complex

2ydn, 4b7u – PfL-LDH + bicine
1cet - PfL-LDH + chloroquine
1t2c - PfL-LDH + NAD
3zh2 - PfL-LDH + DNA aptamer
1ez4 - L-LDH + NAD – Lactobacillus pentosus
1lld, 2ldb - GsL-LDH + NAD
2a92 – PvL-LDH + NAD – Plasmodium vivax
2a94, 2aa3 - PvL-LDH + NAD-analog
1u4o, 1u4s, 1u5a, 1xiv – PfL-LDH + inhibitor
2xxb – TtL-LDH (mutant) + AMP
3pqf – BsL-LDH (mutant) + NAD
3vkv - LcLDH + fructose-bisphosphate
3vpf – LcLDH (mutant) + pyruvate
4aj1, 4aj2, 4aj4, 4aje, 4ajh, 4aji, 4ajj, 4ajk, 4ajl, 4ajn, 4ajo, 4al4 – LDH α chain + inhibitor – rat
4ajp, 4m49 – hLDH α chain + inhibitor - human
4i8x, 4i9h, 4i9n, 4i9u – rLDH A chain + pyridine derivative - rabbit

L-LDH ternary complex with inhibitor

1u5c - PfL-LDH + inhibitor + NAD
1t24, 1t25, 1t26 - PfL-LDH + azole derivative + NAD
1t2e - PfL-LDH (mutant) + oxamate + NAD
1ldg - PfL-LDH + oxamate + NAD
2xxj – TtL-LDH (mutant) + oxamate + NAD
2v7p - TtL-LDH + oxamate + NAD
3om9, 3czm – TgL-LDH + OXQ + NAD
3h3f – rL-LDH A chain + oxamate + NAD
2fnz - CpLDH + oxamate + NAD
1t2f - hL-LDH B chain + azole derivative + NAD
1i0z - hL-LDH H chain + oxamate + NAD
1i10 - hL-LDH M chain + oxamate + NAD
4jnk - hL-LDH A chain + inhibitor + lactate + NAD
3vph - TcLDH + oxamate + NAD + fructose diphosphate
1oc4 – L-LDH + oxamate + NAD – Plasmodium berghei
1a5z - L-LDH + oxamate + NAD – Thermotoga maritima
1lth - L-LDH + oxamate + NAD – Bifidobacterium longum
1ldn - GsL-LDH + oxamate + NAD
9ldb, 9ldt - pL-LDH + oxamate + NAD – pig

L-LDH ternary complex with reactants

1sow, 1pzh - TgL-LDH + oxalate + NAD
1t2d - PfL-LDH + oxalate + NAD
1pzf - TgL-LDH + oxalate + NAD-analog
1pzg - TgL-LDH + sulfate + NAD-analog
3h3j – SaL-LDH (mutant) + pyruvate + NAD
3d4p - SaL-LDH + pyruvate + NAD
2fn7 - CpLDH + lactate + NAD
2ewd - CpLDH + pyruvate + NAD-analog
2fm3 - CpLDH + pyruvate + NAD
5ldh - pLDH + citrate + NAD-analog
3ldh - sdLDH + pyruvate + NAD
3pqd - BsLDH + fructose-bisphosphate + NAD

D-LDHD-LDH

3kb6 – D-LDH + lactate + NAD – Aquifex aeolicus
1j49 – LdD-LDH + sulfate + NAD – Lactobacillus delbrueckii
1j4a - LdD-LDH + sulfate
1f0x – EcD-LDH + FAD – Escherichia coli
2dld - D-LDH + oxamate + NAD – Lactobacillus helveticus

L-LDH IIL-LDH II

1x0a, 1vbi – TtL-LDH II

L-Lactate/malate dehydrogenaseL-Lactate/malate dehydrogenase

1hye, 1hyg – L-LDH/MDH – Methanocaldococcus jannaschi
2g8y - EcL-LDH/MDH

Additional InformationAdditional Information

For additional information, see Carbohydrate Metabolism

ReferenceReference

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

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

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