A lactate dehydrogenase 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) or L-lactate).
Two are cytochrome c-dependent enzymes.
Two are NAD(P)-dependent enzymes.
This article is about the NAD(P)-dependent L-lactate dehydrogenase.
Reactions
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.
Interactive pathway map Click on genes, proteins and metabolites below
to link to respective articles.
Enzyme regulation This protein may use the morpheein model of
allosteric regulation.
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 may ensue in ethanol poisoning.
The increased NADH/NAD+ ratio also can cause hypoglycemia in an 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.
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.
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: LDH-1—in the heart and in RBC
LDH-2—in the reticuloendothelial system LDH-3—in the lungs
LDH-4—in the kidneys, placenta, and pancreas LDH-5—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 subunits, while
H4 is the main isoenzymes for heart muscle in most species, containing four heart 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 suggests myocardial infarction.
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 150000) The H subunit is encoded by LDHB, located
on chromosome 12p12.2-p12.1 150100) A third isoform, LDHC or LDHX, is expressed
only in the testis 150150); its gene is likely a duplicate of LDHA and is also located on
the eleventh chromosome Mutations of the M subunit have been linked
to the rare disease exertional myoglobinuria, 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, 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, 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, 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 test.
Comparison of the measured LDH values with the normal range help guide diagnosis.
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.
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.
These ROS drive cancer cell proliferation by activating kinases that drive cell cycle
progression growth factors at low concentrations, 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, 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, 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.
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 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 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 can help in the distinction between exudates or transudates.
The usual criterion is that a ratio of fluid LDH versus upper limit of normal serum LDH
of more than 0.6 or 2⁄3 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.
HIV LDH is often measured in HIV patients as a
non-specific marker for pneumonia due to Pneumocystis jiroveci.
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 indicated
histoplasmosis in a study of 120 PCP and 30 histoplasmosis patients.
Dysgerminoma 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.
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.
See also Dehydrogenase
Oxidoreductase Notes
References
This article incorporates text from the public domain Pfam and InterPro IPR015409