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632  structures 2619  species 3  interactions 5730  sequences 45  architectures

Family: Ldh_1_N (PF00056)

Summary: lactate/malate dehydrogenase, NAD binding domain

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Lactate dehydrogenase". More...

Lactate dehydrogenase Edit Wikipedia article

Lactate dehydrogenase
1i10.jpg
Lactate dehydrogenase M tetramer (LDH5), Human
Identifiers
EC number 1.1.1.27
CAS number 9001-60-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells (animals, plants, and prokaryotes). LDH catalyzes the conversion of lactate to pyruvic acid and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one molecule to another.

LDH exist in four distinct enzyme classes. This article is specifically about the NAD(P)-dependent L-lactate dehydrogenase. Other LDHs act on D-lactate and/or are dependent on cytochrome c: D-lactate dehydrogenase (cytochrome)) and L-lactate (L-lactate dehydrogenase (cytochrome)).

LDH is expressed 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 such as heart failure.

Reaction

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. It also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer substrate than lactate.

Reaction catalyzed by lactate dehydrogenase
Arrow pushing mechanism for the reaction catalyzed by lactate dehydrogenase

Active site

LDH in humans uses His(193) as the proton acceptor, and works in unison with the coenzyme (Arg99 and Asn138), and substrate (Arg106; Arg169; Thr248) binding residues.[1] The His(193) active site, is not only found in the human form of LDH, but is found in many different animals, showing the convergent evolution of LDH. The two different subunits of LDH: LDHA also known as the M subunit of LDH, and LDHB also known as the H subunit of LDH both retain the same active site, and the same amino acids participating in the reaction. The noticeable difference between the two subunits that make up LDH's tertiary structure is the replacement of alanine (in the M chain) with a glutamine (in the H chain). This tiny but notable change is believed to be the reason the H subunit can bind faster, and the M subunit's catalytic activity isn't reduced when subjected to the same conditions as the H subunit; while the H subunits activity is reduced fivefold.[2]

Isozymes

Lactate dehydrogenase is composed of four subunits (tetramer). The two most common subunits are the LDH-M and LDH-H protein, encoded by the LDHA and LDHB genes, respectively. These two subunits can form five possible tetramers (isoenzymes): 4H, 4M, and the three mixed tetramers (3H1M, 2H2M, 1H3M). These five isoforms are enzymatically similar but show different tissue distribution: 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.

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]

There are two more mammalian LDH subunits that can be included in LDH tetramers: LDHC and LDHBx. LDHC is a testes-specific LDH protein, that is encoded by the LDHC gene. LDHBx is a peroxisome-specific LDH protein. LDHBx is the readthrough-form of LDHB. LDHBx is generated by translation of the LDHB mRNA, but the stop codon is interpreted as an amino acid-encoding codon. In consequence, translation continues to the next stop codon. This leads to the addition of seven amino acid acids to the normal LDH-H protein. The extension contains a peroxisomal targeting signal, so that LDHBx is imported into the peroxisome.[4]

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.[5][6]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
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Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

Enzyme regulation

This protein may use the morpheein model of allosteric regulation.[7]

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.[8]

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.[9]

Genetics

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.

Mutations

This is a mutant version of the LDH-5 enzyme, which is usually found in skeletal muscle

In rare cases, a mutation in the genes controlling the production of lactate dehydrogenase will lead to a medical condition known as lactate dehydrogenase deficiency. Depending on which gene carries the mutation, one of two types will occur: either lactate dehydrogenase-A deficiency (also known as glycogen storage disease XI) or lactate dehydrogenase-B deficiency. Both of these conditions affect how the body breaks down sugars, primarily in certain muscle cells. Lactate dehydrogenase-A deficiency is caused by a mutation to the LDHA gene, while lactate dehydrogenase-B deficiency is caused by a mutation to the LDHB gene.[10]

This condition is inherited in an autosomal recessive pattern, meaning that both parents must contribute a mutated gene in order for this condition to be expressed.[11]

A complete lactate dehydrogenase enzyme consists of four protein subunits.[12] Since the two most common subunits found in lactate dehydrogenase are encoded by the LDHA and LDHB genes, either variation of this disease causes abnormalities in many of the lactate dehydrogenase enzymes found in the body. In the case of lactate dehydrogenase-A deficiency, mutations to the LDHA gene results in the production of an abnormal lactate dehydrogenase-A subunit that cannot bind to the other subunits to form the complete enzyme. This lack of a functional subunit reduces the amount of enzyme formed, leading to an overall decrease in activity. During the anaerobic phase of glycolysis (the Cori Cycle), the mutated enzyme is unable to convert pyruvate into lactate to produce the extra energy the cells need. Since this subunit has the highest concentration in the LDH enzymes found in the skeletal muscles (which are the primary muscles responsible for movement), high-intensity physical activity will lead to an insufficient amount of energy being produced during this anaerobic phase.[13] This in turn will cause the muscle tissue to weaken and eventually break down, a condition known as rhabdomyolysis. The process of rhabdomyolysis also releases myoglobin into the blood, which will eventually end up in the urine and cause it to become red or brown: another condition known as myoglobinuria.[14] Some other common symptoms are exercise intolerance, which consists of fatigue, muscle pain, and cramps during exercise, and skin rashes.[15][16] In severe cases, myoglobinuria can damage the kidneys and lead to life-threatening kidney failure.[17] In order to obtain a definitive diagnosis, a muscle biopsy may be performed to confirm low or absent LDH activity. There is currently no specific treatment for this condition.

In the case of lactate dehydrogenase-B deficiency, mutations to the LDHB gene results in the production of an abnormal lactate dehydrogenase-B subunit that cannot bind to the other subunits to form the complete enzyme. As with lactate dehydrogenase-A deficiency, this mutation reduces the overall effectiveness in the enzyme.[18] However, there are some major differences between these two cases. The first is the location where the condition manifests itself. With lactate dehydrogenase-B deficiency, the highest concentration of B subunits can be found within cardiac muscle, or the heart. Within the heart, lactate dehydrogenase plays the role of converting lactate back into pyruvate so that the pyruvate can be used again to create more energy.[19] With the mutated enzyme, the overall rate of this conversion is decreased. However, unlike lactate dehydrogenase-A deficiency, this mutation does not appear to cause any symptoms or health problems linked to this condition.[16][20] At the present moment, it is unclear why this is the case. Affected individuals are usually discovered only when routine blood tests indicate low LDH levels present within the blood.

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,[21] 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,[22] 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.[23]

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.[24]

Cancer cells

Comparison of LDH activity in normal and cancerous cells

LDH is involved in tumor initiation and metabolism. Cancer cells rely on increased glycolysis resulting in increased lactate production in addition to aerobic respiration in the mitochondria, even under oxygen-sufficient conditions (a process known as the Warburg effect[25]). 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.

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,[26] 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,[27] 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,[28] 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.[29]

Hemolysis

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, i.e. 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 (included in Light's criteria) is that a ratio of fluid LDH versus upper limit of normal serum LDH of more than 0.6[30] or 23[31] 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[32] and 300[32] IU/L.[33] 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.[34] In the case of viral meningitis, high LDH, in general, indicates the presence of encephalitis and poor prognosis.

HIV

LDH is often measured in HIV patients as a non-specific marker for pneumonia due to Pneumocystis jirovecii (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.[35]

Dysgerminoma

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

Prokaryotes

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.[36]

See also

References

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

  1. ^ Holmes RS, Goldberg E (Oct 2009). "Computational analyses of mammalian lactate dehydrogenases: human, mouse, opossum and platypus LDHs". Computational Biology and Chemistry. 33 (5): 379–85. doi:10.1016/j.compbiolchem.2009.07.006. PMC 2777655Freely accessible. PMID 19679512. 
  2. ^ Eventoff W, Rossmann MG, Taylor SS, Torff HJ, Meyer H, Keil W, Kiltz HH (Jul 1977). "Structural adaptations of lactate dehydrogenase isozymes" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 74 (7): 2677–81. doi:10.1073/pnas.74.7.2677. PMC 431242Freely accessible. PMID 197516. 
  3. ^ Van Eerd JP, Kreutzer EK (1996). Klinische Chemie voor Analisten deel 2. pp. 138–139. ISBN 978-90-313-2003-5. 
  4. ^ a b Schueren F, Lingner T, George R, Hofhuis J, Gartner J, Thoms S (2014). "Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals". eLife. 3: e03640. doi:10.7554/eLife.03640. PMID 25247702. 
  5. ^ 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. doi:10.1006/jmbi.1998.2357. PMID 10075524. 
  6. ^ Madern D (2002). "Molecular evolution within the L-malate and L-lactate dehydrogenase super-family.". J Mol Evol. 54 (6): 825–40. doi:10.1007/s00239-001-0088-8. PMID 12029364. 
  7. ^ Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769Freely accessible. PMID 22182754. 
  8. ^ 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. doi:10.1097/00005768-200004000-00007. PMID 10776894. 
  9. ^ 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. doi:10.1073/pnas.1212976110. PMC 3666691Freely accessible. PMID 23650363. 
  10. ^ "Lactate dehydrogenase deficiency". Genetics Home Reference. 2016-02-29. Retrieved 2016-03-02. 
  11. ^ "Diseases - Metabolic Diseases - Causes/Inheritance". Muscular Dystrophy Association. Retrieved 2016-03-02. 
  12. ^ Millar DB, Frattali V, Willick GE (Jun 1969). "The quaternary structure of lactate dehydrogenase. I. The subunit molecular weight and the reversible association at acid pH". Biochemistry. 8 (6): 2416–21. doi:10.1021/bi00834a025. PMID 5816379. 
  13. ^ Kanno T, Sudo K, Maekawa M, Nishimura Y, Ukita M, Fukutake K (Mar 1988). "Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy". Clinica Chimica Acta; International Journal of Clinical Chemistry. 173 (1): 89–98. doi:10.1016/0009-8981(88)90359-2. PMID 3383424. 
  14. ^ "Myoglobinuria; Rhabdomyolysis". neuromuscular.wustl.edu. Retrieved 2016-03-02. 
  15. ^ Hoffmann GF (2002-01-01). Inherited Metabolic Diseases. Lippincott Williams & Wilkins. ISBN 9780781729000. 
  16. ^ a b "Glycogenoses". neuromuscular.wustl.edu. Retrieved 2016-03-02. 
  17. ^ "Glycogen storage disease XI - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-03-02. 
  18. ^ "LDHB gene". Genetics Home Reference. 2016-02-29. Retrieved 2016-03-02. 
  19. ^ "Lactate Dehydrogenase - Worthington Enzyme Manual". www.worthington-biochem.com. Retrieved 2016-03-02. 
  20. ^ "OMIM Entry # 614128 - LACTATE DEHYDROGENASE B DEFICIENCY; LDHBD". www.omim.org. Retrieved 2016-03-02. 
  21. ^ 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. doi:10.1111/j.1748-1716.1978.tb06235.x. PMID 716962. 
  22. ^ 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. doi:10.1152/ajpendo.00303.2003. PMID 14559724. 
  23. ^ Stanford Cancer Center. "Cancer Diagnosis - Understanding Cancer". Understanding Cancer. Stanford Medicine. 
  24. ^ "Lactate dehydrogenase test: MedlinePlus Medical Encyclopedia". MedlinePlus. U.S. National Library of Medicine. 
  25. ^ Warburg O (1956). "On the origin of cancer cells.". Science. 123 (3191): 309–14. doi:10.1126/science.123.3191.309. PMID 13298683. 
  26. ^ Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ (1997). "Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts.". Science. 275 (5306): 1649–52. doi:10.1126/science.275.5306.1649. PMID 9054359. 
  27. ^ 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. doi:10.1021/jf404900y. PMID 24552270. 
  28. ^ 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. doi:10.1016/j.acra.2013.11.014. PMID 24439336. 
  29. ^ 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. doi:10.1159/000357017. PMID 24401755. 
  30. ^ 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. doi:10.1378/chest.111.4.970. PMID 9106577. 
  31. ^ 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. doi:10.7326/0003-4819-77-4-507. PMID 4642731. 
  32. ^ 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. doi:10.1136/thorax.56.11.867. PMC 1745948Freely accessible. PMID 11641512. 
  33. ^ 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. doi:10.1186/1471-2466-2-1. PMC 101409Freely accessible. PMID 11914151. 
  34. ^ Stein JH (1998). Internal Medicine. Elsevier Health Sciences. pp. 1408–. ISBN 978-0-8151-8698-4. Retrieved 12 August 2013. 
  35. ^ 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. 
  36. ^ 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. doi:10.1073/pnas.97.17.9413. PMC 16878Freely accessible. PMID 10944213. 

Further reading

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This is the Wikipedia entry entitled "Malate dehydrogenase". More...

Malate dehydrogenase Edit Wikipedia article

Malate dehydrogenase
Malate dehydrogenase structure.png
Structure of the protein with attached cofactors
Identifiers
EC number 1.1.1.37
CAS number 9001-64-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

Malate dehydrogenase is also involved in gluconeogenesis, the synthesis of glucose from smaller molecules. Pyruvate in the mitochondria is acted upon by pyruvate carboxylase to form oxaloacetate, a citric acid cycle intermediate. In order to get the oxaloacetate out of the mitochondria, malate dehydrogenase reduces it to malate, and it then traverses the inner mitochondrial membrane. Once in the cytosol, the malate is oxidized back to oxaloacetate by cytosolic malate dehydrogenase. Finally, phosphoenolpyruvate carboxykinase (PEPCK) converts oxaloacetate to phosphoenolpyruvate (PEP).

Isozymes

Several isozymes of malate dehydrogenase exist. There are two main isoforms in eukaryotic cells.[1] One is found in the mitochondrial matrix, participating as a key enzyme in the citric acid cycle that catalyzes the oxidation of malate. The other is found in the cytoplasm, assisting the malate-aspartate shuttle with exchanging reducing equivalents so that malate can pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes.[2]

Humans and most other mammals express the following two malate dehydrogenases:

Protein families

Malate dehydrogenases catalyse the interconversion of malate to oxaloacetate. The enzyme participates in the citric acid cycle. The family also contains L-lactate dehydrogenases that catalyse the conversion of L-lactate to pyruvate, the last step in anaerobic glycolysis. 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.[3][4]

Evolution and structure

In most organisms, malate dehydrogenase exists as a homodimeric molecule and is closely related to lactate dehydrogenase in structure. It is a large protein molecule with subunits weighing between 30 and 35 kDa.[5] Based on the amino acid sequences, it seems that MDH has diverged into two main phylogenetic groups that closely resemble either mitochondrial isozymes or cytoplasmic/chloroplast isozymes.[6] Because the sequence identity of malate dehydrogenase in the mitochondria is more closely related to its prokaryotic ancestors in comparison to the cytoplasmic isozyme, the theory that mitochondria and chloroplasts were developed through endosymbiosis is plausible.[7] The amino acid sequences of archaeal MDH are more similar to that of LDH than that of MDH of other organisms. This indicates that there is a possible evolutionary linkage between lactate dehydrogenase and malate dehydrogenase.[8]

Each subunit of the malate dehydrogenase dimer has two distinct domains that vary in structure and functionality. A parallel β-sheet structure makes up the domain, while four β-sheets and one α-helix comprise the central NAD+ binding site. The subunits are held together through extensive hydrogen-bonding and hydrophobic interactions.[9]

Mechanism and activity

The active site of malate dehydrogenase is a hydrophobic cavity within the protein complex that has specific binding sites for the substrate and its coenzyme, NAD+. In its active state, MDH undergoes a conformational change that encloses the substrate to minimize solvent exposure and to position key residues in closer proximity to the substrate.[6] The three residues in particular that comprise a catalytic triad are histidine (His-195), aspartate (Asp-168), both of which work together as a proton transfer system, and arginines (Arg-102, Arg-109, Arg-171), which secure the substrate.[10] Kinetic studies show that MDH enzymatic activity is ordered. NAD+/NADH is bound before the substrate.[11]

Active site of malate dehydrogenase

Allosteric regulation

Because malate dehydrogenase is closely tied to the citric acid cycle, regulation is highly dependent on TCA products. High malate concentrations stimulate MDH activity, and, in a converse manner, high oxaloacetate concentrations inhibit the enzyme.[12] Citrate can both allosterically activate and inhibit the enzymatic activity of MDH. It inhibits the oxidation of malate when there are low levels of malate and NAD+. However, in the presence of high levels of malate and NAD+, citrate can stimulate the production of oxaloacetate. It is believed that there is an allosteric regulatory site on the enzyme where citrate can bind to and drive the reaction equilibrium in either direction.[13]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
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Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

References

  1. ^ Minárik P, Tomásková N, Kollárová M, Antalík M (Sep 2002). "Malate dehydrogenases--structure and function". General Physiology and Biophysics. 21 (3): 257–65. PMID 12537350. 
  2. ^ Musrati RA, Kollárová M, Mernik N, Mikulásová D (Sep 1998). "Malate dehydrogenase: distribution, function and properties". General Physiology and Biophysics. 17 (3): 193–210. PMID 9834842. 
  3. ^ Chapman AD, Cortés A, Dafforn TR, Clarke AR, Brady RL (Jan 1999). "Structural basis of substrate specificity in malate dehydrogenases: crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase, alpha-ketomalonate and tetrahydoNAD". Journal of Molecular Biology. 285 (2): 703–12. doi:10.1006/jmbi.1998.2357. PMID 10075524. 
  4. ^ Madern D (Jun 2002). "Molecular evolution within the L-malate and L-lactate dehydrogenase super-family". Journal of Molecular Evolution. 54 (6): 825–40. doi:10.1007/s00239-001-0088-8. PMID 12029364. 
  5. ^ Banaszak LJ, Bradshaw RA (1975). "Malate dehydrogenase". In Boyer PD. The Enzymes. 11 (3rd ed.). New York: Academic Press. pp. 369–396. 
  6. ^ a b Goward CR, Nicholls DJ (Oct 1994). "Malate dehydrogenase: a model for structure, evolution, and catalysis". Protein Science. 3 (10): 1883–8. doi:10.1002/pro.5560031027. PMC 2142602Freely accessible. PMID 7849603. 
  7. ^ McAlister-Henn L (May 1988). "Evolutionary relationships among the malate dehydrogenases". Trends in Biochemical Sciences. 13 (5): 178–81. doi:10.1016/0968-0004(88)90146-6. PMID 3076279. 
  8. ^ Cendrin F, Chroboczek J, Zaccai G, Eisenberg H, Mevarech M (Apr 1993). "Cloning, sequencing, and expression in Escherichia coli of the gene coding for malate dehydrogenase of the extremely halophilic archaebacterium Haloarcula marismortui". Biochemistry. 32 (16): 4308–13. doi:10.1021/bi00067a020. PMID 8476859. 
  9. ^ Hall MD, Levitt DG, Banaszak LJ (Aug 1992). "Crystal structure of Escherichia coli malate dehydrogenase. A complex of the apoenzyme and citrate at 1.87 A resolution". Journal of Molecular Biology. 226 (3): 867–82. doi:10.1016/0022-2836(92)90637-Y. PMID 1507230. 
  10. ^ Lamzin VS, Dauter Z, Wilson KS (May 1994). "Dehydrogenation through the looking-glass". Nature Structural Biology. 1 (5): 281–2. doi:10.1038/nsb0594-281. PMID 7664032. 
  11. ^ Shows TB, Chapman VM, Ruddle FH (Dec 1970). "Mitochondrial malate dehydrogenase and malic enzyme: Mendelian inherited electrophoretic variants in the mouse". Biochemical Genetics. 4 (6): 707–18. doi:10.1007/BF00486384. PMID 5496232. 
  12. ^ Mullinax TR, Mock JN, McEvily AJ, Harrison JH (Nov 1982). "Regulation of mitochondrial malate dehydrogenase. Evidence for an allosteric citrate-binding site". The Journal of Biological Chemistry. 257 (22): 13233–9. PMID 7142142. 
  13. ^ Gelpí JL, Dordal A, Montserrat J, Mazo A, Cortés A (Apr 1992). "Kinetic studies of the regulation of mitochondrial malate dehydrogenase by citrate". The Biochemical Journal. 283 (Pt 1): 289–97. doi:10.1042/bj2830289. PMC 1131027Freely accessible. PMID 1567375. 

Further reading

  • Guha A, Englard S, Listowsky I (Feb 1968). "Beef heart malic dehydrogenases. VII. Reactivity of sulfhydryl groups and conformation of the supernatant enzyme". The Journal of Biological Chemistry. 243 (3): 609–15. PMID 5637713. 
  • McReynolds MS, Kitto GB (Feb 1970). "Purification and properties of Drosophila malate dehydrogenases". Biochimica et Biophysica Acta. 198 (2): 165–75. doi:10.1016/0005-2744(70)90048-3. PMID 4313528. 
  • Wolfe RG, Neilands JB (Jul 1956). "Some molecular and kinetic properties of heart malic dehydrogenase". The Journal of Biological Chemistry. 221 (1): 61–9. PMID 13345798. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

lactate/malate dehydrogenase, NAD binding domain Provide feedback

L-lactate dehydrogenases are metabolic enzymes which catalyse the conversion of L-lactate to pyruvate, the last step in anaerobic glycolysis. L-2-hydroxyisocaproate dehydrogenases are also members of the family. Malate dehydrogenases catalyse the interconversion of malate to oxaloacetate. The enzyme participates in the citric acid cycle. L-lactate dehydrogenase is also found as a lens crystallin in bird and crocodile eyes. N-terminus (this family) is a Rossmann NAD-binding fold. C-terminus is an unusual alpha+beta fold.

Literature references

  1. Chapman AD, Cortes A, Dafforn TR, Clarke AR, Brady RL; , J Mol Biol 1999;285:703-712.: Structural basis of substrate specificity in malate dehydrogenases: crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase, alpha-ketomalonate and tetrahydoNAD. PUBMED:10075524 EPMC:10075524

  2. Madern D; , J Mol Evol 2002;54:825-840.: Molecular evolution within the L-malate and L-lactate dehydrogenase super-family. PUBMED:12029364 EPMC:12029364


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001236

L-lactate dehydrogenases are metabolic enzymes which catalyse the conversion of L-lactate to pyruvate, the last step in anaerobic glycolysis [PUBMED:11276087]. L-lactate dehydrogenase is also found as a lens crystallin in bird and crocodile eyes. L-2-hydroxyisocaproate dehydrogenases are also members of the family. Malate dehydrogenases catalyse the interconversion of malate to oxaloacetate [PUBMED:8117664]. The enzyme participates in the citric acid cycle.

This entry represents the N-terminal, and is thought to be a Rossmann NAD-binding fold.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan NADP_Rossmann (CL0063), which has the following description:

A class of redox enzymes are two domain proteins. One domain, termed the catalytic domain, confers substrate specificity and the precise reaction of the enzyme. The other domain, which is common to this class of redox enzymes, is a Rossmann-fold domain. The Rossmann domain binds nicotinamide adenine dinucleotide (NAD+) and it is this cofactor that reversibly accepts a hydride ion, which is lost or gained by the substrate in the redox reaction. Rossmann domains have an alpha/beta fold, which has a central beta sheet, with approximately five alpha helices found surrounding the beta sheet.The strands forming the beta sheet are found in the following characteristic order 654123. The inter sheet crossover of the stands in the sheet form the NAD+ binding site [1]. In some more distantly relate Rossmann domains the NAD+ cofactor is replaced by the functionally similar cofactor FAD.

The clan contains the following 184 members:

2-Hacid_dh_C 3Beta_HSD 3HCDH_N adh_short adh_short_C2 ADH_zinc_N ADH_zinc_N_2 AdoHcyase_NAD AdoMet_MTase AlaDh_PNT_C Amino_oxidase ApbA AviRa B12-binding Bac_GDH Bin3 Bmt2 CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_N DFP DNA_methylase DOT1 DREV DUF1442 DUF166 DUF1776 DUF2431 DUF268 DUF364 DUF43 DUF5129 DUF5130 DUF938 DXP_redisom_C DXP_reductoisom Eco57I ELFV_dehydrog Eno-Rase_FAD_bd Eno-Rase_NADH_b Enoyl_reductase Epimerase F420_oxidored FAD_binding_2 FAD_binding_3 FAD_oxidored Fibrillarin FMO-like FmrO FtsJ G6PD_N GCD14 GDI GDP_Man_Dehyd GFO_IDH_MocA GIDA GidB GLF Glu_dehyd_C Glyco_hydro_4 GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN K_oxygenase KR LCM Ldh_1_N Lycopene_cycl Malic_M Mannitol_dh MCRA Met_10 Methyltr_RsmB-F Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_15 Methyltransf_16 Methyltransf_17 Methyltransf_18 Methyltransf_19 Methyltransf_2 Methyltransf_20 Methyltransf_21 Methyltransf_22 Methyltransf_23 Methyltransf_24 Methyltransf_25 Methyltransf_28 Methyltransf_29 Methyltransf_3 Methyltransf_30 Methyltransf_31 Methyltransf_32 Methyltransf_34 Methyltransf_4 Methyltransf_5 Methyltransf_7 Methyltransf_8 Methyltransf_9 Methyltransf_PK MethyltransfD12 MetW Mg-por_mtran_C MOLO1 Mqo MT-A70 MTS Mur_ligase N2227 N6-adenineMlase N6_Mtase N6_N4_Mtase NAD_binding_10 NAD_binding_2 NAD_binding_3 NAD_binding_4 NAD_binding_5 NAD_binding_7 NAD_binding_8 NAD_binding_9 NAD_Gly3P_dh_N NAS NmrA NNMT_PNMT_TEMT NodS NSP13 OCD_Mu_crystall PARP_regulatory PCMT PDH Polysacc_synt_2 Pox_MCEL Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Sacchrp_dh_NADP SAM_MT SAMBD SE Semialdhyde_dh Shikimate_DH Spermine_synth TehB THF_DHG_CYH_C Thi4 ThiF TPM_phosphatase TPMT TrkA_N TRM TRM13 TrmK tRNA_U5-meth_tr Trp_halogenase TylF Ubie_methyltran UDPG_MGDP_dh_N UPF0020 UPF0146 V_cholerae_RfbT XdhC_C YjeF_N

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(25)
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(5730)
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(25081)
NCBI
(25584)
Meta
(2554)
RP15
(1325)
RP35
(3593)
RP55
(5993)
RP75
(8916)
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  Seed
(25)
Full
(5730)
Representative proteomes UniProt
(25081)
NCBI
(25584)
Meta
(2554)
RP15
(1325)
RP35
(3593)
RP55
(5993)
RP75
(8916)
Alignment:
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  Seed
(25)
Full
(5730)
Representative proteomes UniProt
(25081)
NCBI
(25584)
Meta
(2554)
RP15
(1325)
RP35
(3593)
RP55
(5993)
RP75
(8916)
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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Overington enriched
Previous IDs: ldh;
Type: Family
Author: Bateman A, Eddy SR, Griffiths-Jones SR
Number in seed: 25
Number in full: 5730
Average length of the domain: 139.40 aa
Average identity of full alignment: 30 %
Average coverage of the sequence by the domain: 42.65 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 20.5 20.5
Noise cut-off 20.4 20.4
Model length: 141
Family (HMM) version: 21
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Species distribution

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Archea Archea Eukaryota Eukaryota
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Interactions

There are 3 interactions for this family. More...

Ldh_1_N Ldh_1_C Ldh_1_C

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ldh_1_N domain has been found. There are 632 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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