Summary: D-lactate dehydrogenase, membrane binding
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Lactate dehydrogenase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|lactate dehydrogenase A
|Locus||Chr. 11 p15.4|
|lactate dehydrogenase B
|Locus||Chr. 12 p12.2-12.1|
|lactate dehydrogenase C|
|Locus||Chr. 11 p15.5-15.3|
|D-lactate dehydrogenase, membrane binding|
crystal structure of d-lactate dehydrogenase, a peripheral membrane respiratory enzyme.
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.
- 1 Reactions
- 2 Interactive pathway map
- 3 Enzyme regulation
- 4 Enzyme isoforms
- 5 Genetics in humans
- 6 Medical use
- 7 Prokaryotes
- 8 See also
- 9 References
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.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
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.
Functional lactate dehydrogenase are homo or hetero tetramers composed of M and H protein subunits encoded by the LDHA and LDHB genes, respectively:
- LDH-1 (4H)—in the heart and in RBC (red blood cells)
- LDH-2 (3H1M)—in the reticuloendothelial system
- LDH-3 (2H2M)—in the lungs
- LDH-4 (1H3M)—in the kidneys, placenta, and pancreas
- LDH-5 (4M)—in the liver and striated muscle
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:
- The M subunit is encoded by LDHA, located on chromosome 11p15.4 (Online 'Mendelian Inheritance in Man' (OMIM) 150000)
- The H subunit is encoded by LDHB, located on chromosome 12p12.2-p12.1 (Online 'Mendelian Inheritance in Man' (OMIM) 150100)
- A third isoform, LDHC or LDHX, is expressed only in the testis (Online 'Mendelian Inheritance in Man' (OMIM) 150150); its gene is likely a duplicate of LDHA and is also located on the eleventh chromosome (11p15.5-p15.3)
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.
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, and lung or liver disease.
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. 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.
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.
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 or ⅔ 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 and 300 IU/L. 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.
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.
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.
- 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 3298769. PMID 22182754.
- 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.
- Stanford Cancer Center. "Cancer Diagnosis - Understanding Cancer". Understanding Cancer. Stanford Medicine.
- "Lactate dehydrogenase test: MedlinePlus Medical Encyclopedia". MedlinePlus. U.S. National Library of Medicine.
- 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.
- 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.
- 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 1745948. PMID 11641512.
- 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 101409. PMID 11914151.
- Stein JH (1998). Internal Medicine. Elsevier Health Sciences. pp. 1408–. ISBN 978-0-8151-8698-4. Retrieved 12 August 2013.
- 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.
- 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 16878. PMID 10944213.
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D-lactate dehydrogenase, membrane binding Provide feedback
Members of this family are predominantly found in prokaryotic D-lactate dehydrogenase, forming the cap-membrane-binding domain, which consists of a large seven-stranded antiparallel beta-sheet flanked on both sides by alpha-helices. They allow for membrane association .
Dym O, Pratt EA, Ho C, Eisenberg D; , Proc Natl Acad Sci U S A. 2000;97:9413-9418.: The crystal structure of D-lactate dehydrogenase, a peripheral membrane respiratory enzyme. PUBMED:10944213 EPMC:10944213
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR015409
Members of this entry are predominantly found in prokaryotic D-lactate dehydrogenase, forming the cap-membrane-binding domain, which consists of a large seven-stranded antiparallel beta-sheet flanked on both sides by alpha-helices. They allow for membrane association [PUBMED:10944213].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||flavin adenine dinucleotide binding (GO:0050660)|
|Biological process||transmembrane transport (GO:0055085)|
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This clan consists of a duplicated subdomain in a variety of FAD-liked oxidase/dehydrogenase enzymes.
The clan contains the following 6 members:ALO BBE Chol_subst-bind Cytokin-bind FAD-oxidase_C Lact-deh-memb
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Number in seed:||19|
|Number in full:||896|
|Average length of the domain:||277.90 aa|
|Average identity of full alignment:||68 %|
|Average coverage of the sequence by the domain:||51.68 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||6|
|Download:||download the raw HMM for this family|
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There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Lact-deh-memb domain has been found. There are 2 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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