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Lactate dehydrogenase

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Lactate dehydrogenase
Identifiers
EC no.1.1.1.27
CAS no.9001-60-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
lactate dehydrogenase A
(subunit M)
Human lactate dehydrogenase M4 (the isoenzyme found in skeletal muscle). From PDB: 1I10​.
Identifiers
SymbolLDHA
Alt. symbolsLDHM
NCBI gene3939
HGNC6535
OMIM150000
RefSeqNM_005566
UniProtP00338
Other data
EC number1.1.1.27
LocusChr. 11 p15.4
Search for
StructuresSwiss-model
DomainsInterPro
lactate dehydrogenase B
(subunit H)
Identifiers
SymbolLDHB
Alt. symbolsLDHL
NCBI gene3945
HGNC6541
OMIM150100
RefSeqNM_002300
UniProtP07195
Other data
EC number1.1.1.27
LocusChr. 12 p12.2-12.1
Search for
StructuresSwiss-model
DomainsInterPro
lactate dehydrogenase C
Identifiers
SymbolLDHC
NCBI gene3948
HGNC6544
OMIM150150
RefSeqNM_002301
UniProtP07864
Other data
EC number1.1.1.27
LocusChr. 11 p15.5-15.3
Search for
StructuresSwiss-model
DomainsInterPro
D-lactate dehydrogenase, membrane binding
crystal structure of d-lactate dehydrogenase, a peripheral membrane respiratory enzyme.
Identifiers
SymbolLact-deh-memb
PfamPF09330
Pfam clanCL0277
InterProIPR015409
SCOP21f0x / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Lactate dehydrogenase (LDH or LD) is an enzyme (EC 1.1.1.27) present in a wide variety of organisms, including plants and animals.

Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate (EC 1.1.2.4) or L-lactate (EC 1.1.2.3). The other two are NAD(P)-dependent enzymes, each acting on either D-lactate (EC 1.1.1.28) or L-lactate (EC 1.1.1.27). This article is about the NAD(P)-dependent L-lactate dehydrogenase.

Reactions

Catalytic function of LDH

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. There is little to no activity with beta-hydroxybutyrate.

Enzyme regulation

This protein may use the morpheein model of allosteric regulation. [1]

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, hypoglycemia and anion-gap metabolic acidosis (lactic acidosis) may ensue in ethanol poisoning.

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.

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.

Medical use

Tissue breakdown releases LDH, and therefore LDH can be measured as a surrogate for tissue breakdown, e.g. hemolysis. Other disorders indicated by elevated LDH include cancer, meningitis, encephalitis, acute pancreatitis, and HIV.

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) 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[3] or 2⁄3[4] 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[5] and 300[5] IU/L.[6] 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. 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 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.[7]

Dysgerminoma

Elevated LDH is often the first clinical sign of 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.[8]

See also

References

  1. ^ T. Selwood and E. K. Jaffe. (2011). "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. PMID 22182754.
  2. ^ 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.{{cite book}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  3. ^ Heffner J, Brown L, Barbieri C (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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Light R, Macgregor M, Luchsinger P, Ball W (1972). "Pleural effusions: the diagnostic separation of transudates and exudates". Ann Intern Med. 77 (4): 507–13. PMID 4642731.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b Joseph J, Badrinath P, Basran GS, Sahn SA (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 1745948. PMID 11641512. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1186/1471-2466-2-1, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1186/1471-2466-2-1 instead. [1]
  7. ^ Butt AA, Michaels S, Greer D, Clark R, Kissinger P, Martin DH (2002). "Serum LDH level as a clue to the diagnosis of histoplasmosis". AIDS Read. 12 (7): 317–21. PMID 12161854. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Dym O, Pratt EA, Ho C, Eisenberg D (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)


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