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Lactate dehydrogenase

Lactate dehydrogenase
EC number
CAS number 9001-60-9
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

A lactate dehydrogenase (LDH or LD) is an enzyme found in animals, plants, and prokaryotes.

Lactate dehydrogenase is of medical significance because it is found extensively in body tissues, such as blood cells and heart muscle. Because it is released during tissue damage, it is a marker of common injuries and disease.

A dehydrogenase is an enzyme that transfers a hydride from one molecule to another. Lactate dehydrogenase catalyzes the conversion of pyruvate to lactate and back, as it converts NADH to NAD+ and back.

Lactate dehydrogenases exist in four distinct enzyme classes. Each one acts on either D-lactate (D-lactate dehydrogenase (cytochrome)) or L-lactate (L-lactate dehydrogenase (cytochrome)). Two are cytochrome c-dependent enzymes. Two are NAD(P)-dependent enzymes. This article is about the NAD(P)-dependent L-lactate dehydrogenase.

Human isozymes


File:Reaction catalyzed by lactate dehydrogenase.png
Reaction catalyzed by lactate dehydrogenase

Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. It converts pyruvate, the final product of glycolysis, to lactate when oxygen is absent or in short supply, and it performs the reverse reaction during the Cori cycle in the liver. At high concentrations of lactate, the enzyme exhibits feedback inhibition, and the rate of conversion of pyruvate to lactate is decreased.

File:Lactate dehydrogenase mechanism.png
Arrow pushing mechanism for the reaction catalyzed by lactate dehydrogenase

It also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer substrate than lactate. There is little to no activity with beta-hydroxybutyrate.

Protein families

The family also contains L-lactate dehydrogenases that catalyse the conversion of L-lactate to pyruvate, the last step in anaerobic glycolysis. Malate dehydrogenases that catalyse the interconversion of malate to oxaloacetate and participate in the citric acid cycle, and L-2-hydroxyisocaproate dehydrogenases are also members of the family. The N-terminus is a Rossmann NAD-binding fold and the C-terminus is an unusual alpha+beta fold.[1][2]

Interactive pathway map

Template:GlycolysisGluconeogenesis WP534

Enzyme regulation

This protein may use the morpheein model of allosteric regulation.[3]

Ethanol-induced hypoglycemia

Ethanol is dehydrogenated to acetaldehyde by alcohol dehydrogenase, and further into acetic acid by acetaldehyde dehydrogenase. During this reaction 2 NADH are produced. If large amounts of ethanol are present, then large amounts of NADH are produced, leading to a depletion of NAD+. Thus, the conversion of pyruvate to lactate is increased due to the associated regeneration of NAD+. Therefore, anion-gap metabolic acidosis (lactic acidosis) may ensue in ethanol poisoning.

The increased NADH/NAD+ ratio also can cause hypoglycemia in an (otherwise) fasting individual who has been drinking and is dependent on gluconeogenesis to maintain blood glucose levels. Alanine and lactate are major gluconeogenic precursors that enter gluconeogenesis as pyruvate. The high NADH/NAD+ ratio shifts the lactate dehydrogenase equilibrium to lactate, so that less pyruvate can be formed and, therefore, gluconeogenesis is impaired.

Substrate regulation

LDH is also regulated by the relative concentrations of its substrates. LDH becomes more active under periods of extreme muscular output due to an increase in substrates for the LDH reaction. When skeletal muscles are pushed to produce high levels of power, the demand for ATP in regards to aerobic ATP supply leads to an accumulation of free ADP, AMP, and Pi. The subsequent glycolytic flux, specifically production of NADH and pyruvate, exceeds the capacity for pyruvate dehydrogenase and other shuttle enzymes to metabolize pyruvate. The flux through LDH increases in response to increased levels of pyruvate and NADH to metabolize pyruvate into lactate.[4]

Transcriptional regulation

LDH undergoes transcriptional regulation by PGC-1α. PGC-1α regulates LDH by decreasing LDH A mRNA transcription and the enzymatic activity of pyruvate to lactate conversion.[5]

Enzyme isoforms

Functional lactate dehydrogenase are homo or hetero tetramers composed of M and H protein subunits encoded by the LDHA and LDHB genes, respectively:

The five isoenzymes that are usually described in the literature each contain four subunits. The major isoenzymes of skeletal muscle and liver, M4, has four muscle (M) subunits, while H4 is the main isoenzymes for heart muscle in most species, containing four heart (H) subunits. The other variants contain both types of subunits.

Usually LDH-2 is the predominant form in the serum. A LDH-1 level higher than the LDH-2 level (a "flipped pattern") suggests myocardial infarction (damage to heart tissues releases heart LDH, which is rich in LDH-1, into the bloodstream). The use of this phenomenon to diagnose infarction has been largely superseded by the use of Troponin I or T measurement.[citation needed]

Genetics in humans

The M and H subunits are encoded by two different genes:

Mutations of the M subunit have been linked to the rare disease exertional myoglobinuria (see OMIM article), and mutations of the H subunit have been described but do not appear to lead to disease.

Role in muscular fatigue

The onset of acidosis during periods of intense exercise is commonly been attributed to accumulation of lactic acid. From this reasoning, the idea of lactate production being a primary cause of muscle fatigue during exercise has been widely adopted. A closer, mechanistic analysis of lactate production under anaerobic conditions shows that there is no biochemical evidence for the production of lactate through LDH contributing to acidosis. While LDH activity is correlated to muscle fatigue,[7] the production of lactate by means of the LDH complex works as a system to delay the onset of muscle fatigue.

LDH works to prevent muscular failure and fatigue in multiple ways. The lactate-forming reaction generates cytosolic NAD+, which feeds into the glyceraldehyde 3-phosphate dehydrogenase reaction to help maintain cytosolic redox potential and promote substrate flux through the second phase of glycolysis to promote ATP generation. This, in effect, provides more energy to contracting muscles under heavy workloads. The production and removal of lactate from the cell also ejects a proton consumed in the LDH reaction- the removal of excess protons produced in the wake of this fermentation reaction serves to act as a buffer system for muscle acidosis. Once proton accumulation exceeds the rate of uptake in lactate production and removal through the LDH symport,[8] muscular acidosis occurs.

Medical relevance

LDH is a protein that normally appears throughout the body in small amounts. Many cancers can raise LDH levels, so LDH may be used as a tumor marker, but at the same time, it is not useful in identifying a specific kind of cancer. Measuring LDH levels can be helpful in monitoring treatment for cancer. Noncancerous conditions that can raise LDH levels include heart failure, hypothyroidism, anemia, pre-eclampsia, meningitis, encephalitis, acute pancreatitis, HIV and lung or liver disease.[9]

Tissue breakdown releases LDH, and therefore LDH can be measured as a surrogate for tissue breakdown, e.g. hemolysis. LDH is measured by the lactate dehydrogenase (LDH) test (also known as the LDH test or Lactic acid dehydrogenase test). Comparison of the measured LDH values with the normal range help guide diagnosis.[10]

Cancer cells

LDH is involved in tumor initiation and metabolism. Cancer cells rely on anaerobic respiration for the conversion of glucose to lactate even under oxygen-sufficient conditions (a process known as the Warburg effect[11]). This state of fermentative glycolysis is catalyzed by the A form of LDH. This mechanism allows tumorous cells to convert the majority of their glucose stores into lactate regardless of oxygen availability, shifting use of glucose metabolites from simple energy production to the promotion of accelerated cell growth and replication. For this reason, LDH A and the possibility of inhibiting its activity has been identified as a promising target in cancer treatments focused on preventing carcinogenic cells from proliferating.

File:LDH activity- normal vs canceous cells.png
Comparison of LDH activity in normal and cancerous cell metabolisms

Chemical inhibition of LDH A has demonstrated marked changes in metabolic processes and overall survival carcinoma cells. Oxamate is a cytosolic inhibitor of LDH A that significantly decreases ATP production in tumorous cells as well as increasing production of reactive oxygen species (ROS). These ROS drive cancer cell proliferation by activating kinases that drive cell cycle progression growth factors at low concentrations,[12] but can damage DNA through oxidative stress at higher concentrations. Secondary lipid oxidation products can also inactivate LDH and impact its ability to regenerate NADH,[13] directly disrupting the enzymes ability to convert lactate to pyruvate.

While recent studies have shown that LDH activity is not necessarily an indicator of metastatic risk,[14] LDH expression can act as a general marker in the prognosis of cancers. Expression of LDH5 and VEGF in tumors and the stroma has been found to be a strong prognostic factor for diffuse or mixed-type gastric cancers.[15]


In medicine, LDH is often used as a marker of tissue breakdown as LDH is abundant in red blood cells and can function as a marker for hemolysis. A blood sample that has been handled incorrectly can show false-positively high levels of LDH due to erythrocyte damage.

It can also be used as a marker of myocardial infarction. Following a myocardial infarction, levels of LDH peak at 3–4 days and remain elevated for up to 10 days. In this way, elevated levels of LDH (where the level of LDH1 is higher than that of LDH2, ie the LDH Flip, as normally, in serum, LDH2 is higher than LDH1) can be useful for determining whether a patient has had a myocardial infarction if they come to doctors several days after an episode of chest pain.

Tissue turnover

Other uses are assessment of tissue breakdown in general; this is possible when there are no other indicators of hemolysis. It is used to follow-up cancer (especially lymphoma) patients, as cancer cells have a high rate of turnover with destroyed cells leading to an elevated LDH activity.

Exudates and transudates

Measuring LDH in fluid aspirated from a pleural effusion (or pericardial effusion) can help in the distinction between exudates (actively secreted fluid, e.g. due to inflammation) or transudates (passively secreted fluid, due to a high hydrostatic pressure or a low oncotic pressure). The usual criterion is that a ratio of fluid LDH versus upper limit of normal serum LDH of more than 0.6[16] or 23[17] indicates an exudate, while a ratio of less indicates a transudate. Different laboratories have different values for the upper limit of serum LDH, but examples include 200[18] and 300[18] IU/L.[19] In empyema, the LDH levels, in general, will exceed 1000 IU/L.

Meningitis and encephalitis

High levels of lactate dehydrogenase in cerebrospinal fluid are often associated with bacterial meningitis.[20] In the case of viral meningitis, high LDH, in general, indicates the presence of encephalitis and poor prognosis.


LDH is often measured in HIV patients as a non-specific marker for pneumonia due to Pneumocystis jiroveci (PCP). Elevated LDH in the setting of upper respiratory symptoms in an HIV patient suggests, but is not diagnostic for, PCP. However, in HIV-positive patients with respiratory symptoms, a very high LDH level (>600 IU/L) indicated histoplasmosis (9.33 more likely) in a study of 120 PCP and 30 histoplasmosis patients.[21]


Elevated LDH is often the first clinical sign of a rare malignant cell tumor called a dysgerminoma. Not all dysgerminomas produce LDH, and this is often a non-specific finding.


A cap-membrane-binding domain is found in prokaryotic lactate dehydrogenase. This consists of a large seven-stranded antiparallel beta-sheet flanked on both sides by alpha-helices. It allows for membrane association.[22]

See also


  1. ^ Chapman AD, Cortés A, Dafforn TR, Clarke AR, Brady RL (1999). "Structural basis of substrate specificity in malate dehydrogenases: crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase, alpha-ketomalonate and tetrahydoNAD.". J Mol Biol 285 (2): 703–12. PMID 10075524. doi:10.1006/jmbi.1998.2357. 
  2. ^ Madern D (2002). "Molecular evolution within the L-malate and L-lactate dehydrogenase super-family.". J Mol Evol 54 (6): 825–40. PMID 12029364. doi:10.1007/s00239-001-0088-8. 
  3. ^ Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. PMC 3298769. PMID 22182754. doi:10.1016/ 
  4. ^ Spriet LL, Howlett RA, Heigenhauser GJ (2000). "An enzymatic approach to lactate production in human skeletal muscle during exercise.". Med Sci Sports Exerc 32 (4): 756–63. PMID 10776894. doi:10.1097/00005768-200004000-00007. 
  5. ^ Summermatter S, Santos G, Pérez-Schindler J, Handschin C (2013). "Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A.". Proc Natl Acad Sci U S A 110 (21): 8738–43. PMC 3666691. PMID 23650363. doi:10.1073/pnas.1212976110. 
  6. ^ Van Eerd, J. P. F. M.; Kreutzer, E. K. J. (1996). Klinische Chemie voor Analisten deel 2. pp. 138–139. ISBN 978-90-313-2003-5. 
  7. ^ Tesch P, Sjödin B, Thorstensson A, Karlsson J (1978). "Muscle fatigue and its relation to lactate accumulation and LDH activity in man.". Acta Physiol Scand 103 (4): 413–20. PMID 716962. doi:10.1111/j.1748-1716.1978.tb06235.x. 
  8. ^ Juel C, Klarskov C, Nielsen JJ, Krustrup P, Mohr M, Bangsbo J (2004). "Effect of high-intensity intermittent training on lactate and H+ release from human skeletal muscle.". Am J Physiol Endocrinol Metab 286 (2): E245–51. PMID 14559724. doi:10.1152/ajpendo.00303.2003. 
  9. ^ Stanford Cancer Center. "Cancer Diagnosis - Understanding Cancer". Understanding Cancer. Stanford Medicine. 
  10. ^ "Lactate dehydrogenase test: MedlinePlus Medical Encyclopedia". MedlinePlus. U.S. National Library of Medicine. 
  11. ^ Warburg O (1956). "On the origin of cancer cells.". Science 123 (3191): 309–14. PMID 13298683. doi:10.1126/science.123.3191.309. 
  12. ^ Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER et al. (1997). "Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts.". Science 275 (5306): 1649–52. PMID 9054359. doi:10.1126/science.275.5306.1649. 
  13. ^ Ramanathan R, Mancini RA, Suman SP, Beach CM (2014). "Covalent Binding of 4-Hydroxy-2-nonenal to Lactate Dehydrogenase Decreases NADH Formation and Metmyoglobin Reducing Activity.". J Agric Food Chem 62 (9): 2112–7. PMID 24552270. doi:10.1021/jf404900y. 
  14. ^ Xu HN, Kadlececk S, Profka H, Glickson JD, Rizi R, Li LZ (2014). "Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized (13)C-Pyruvate.". Acad Radiol 21 (2): 223–31. PMID 24439336. doi:10.1016/j.acra.2013.11.014. 
  15. ^ Kim HS, Lee HE, Yang HK, Kim WH (2014). "High lactate dehydrogenase 5 expression correlates with high tumoral and stromal vascular endothelial growth factor expression in gastric cancer.". Pathobiology 81 (2): 78–85. PMID 24401755. doi:10.1159/000357017. 
  16. ^ Heffner JE, Brown LK, Barbieri CA (April 1997). "Diagnostic value of tests that discriminate between exudative and transudative pleural effusions. Primary Study Investigators". Chest 111 (4): 970–80. PMID 9106577. doi:10.1378/chest.111.4.970. 
  17. ^ Light RW, Macgregor MI, Luchsinger PC, Ball WC (October 1972). "Pleural effusions: the diagnostic separation of transudates and exudates". Ann. Intern. Med. 77 (4): 507–13. PMID 4642731. doi:10.7326/0003-4819-77-4-507. 
  18. ^ a b Joseph J, Badrinath P, Basran GS, Sahn SA (November 2001). "Is the pleural fluid transudate or exudate? A revisit of the diagnostic criteria". Thorax 56 (11): 867–70. PMC 1745948. PMID 11641512. doi:10.1136/thorax.56.11.867. 
  19. ^ Joseph J, Badrinath P, Basran GS, Sahn SA (March 2002). "Is albumin gradient or fluid to serum albumin ratio better than the pleural fluid lactate dehydroginase in the diagnostic of separation of pleural effusion?". BMC Pulm Med 2: 1. PMC 101409. PMID 11914151. doi:10.1186/1471-2466-2-1. 
  20. ^ Stein JH (1998). Internal Medicine. Elsevier Health Sciences. pp. 1408–. ISBN 978-0-8151-8698-4. Retrieved 12 August 2013. 
  21. ^ Butt AA, Michaels S, Greer D, Clark R, Kissinger P, Martin DH (July 2002). "Serum LDH level as a clue to the diagnosis of histoplasmosis". AIDS Read 12 (7): 317–21. PMID 12161854. 
  22. ^ Dym O, Pratt EA, Ho C, Eisenberg D (August 2000). "The crystal structure of D-lactate dehydrogenase, a peripheral membrane respiratory enzyme". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9413–8. PMC 16878. PMID 10944213. doi:10.1073/pnas.97.17.9413. 

Further reading


This article incorporates text from the public domain Pfam and InterPro IPR015409