Lactate dehydrogenase (LDH) stands as a pivotal enzyme within the anaerobic metabolic pathway, catalyzing the reversible conversion of lactate to pyruvate while facilitating the reduction of NAD+ to NADH and vice versa. Ubiquitously distributed across various organisms, LDH plays a crucial role in gluconeogenesis and DNA metabolism, making it a vital checkpoint in cellular processes. Despite its conservation in structure across species, LDH exhibits differential expression in tissues, reflected in its isozymes LDH-1 through LDH-5. While LDH serves as a marker for tissue turnover and pathology, its non-specificity and susceptibility to artifacts hinder its clinical utility, necessitating complementary assays for accurate diagnoses.
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Understanding LDH at Cellular and Molecular Levels
At the cellular level, LDH is a widely distributed cytoplasmic enzyme found in nearly all tissues, with higher concentrations in muscle, liver, and kidney. Red blood cells also contain moderate levels of LDH. LDH exists in five isomeric forms, organized in tetramers composed of muscle (M) and heart (H) subunits. These isozymes, named LDH-1 through LDH-5, exhibit tissue-specific expression patterns. For instance, LDH-1, composed of four heart subunits, predominates in heart tissue, while LDH-5, consisting of four muscle subunits, is prominently expressed in liver and skeletal muscle. Despite catalyzing the same reaction, these isoforms differ in substrate affinity, inhibition concentration, isoelectric point, and electrophoretic mobility, as revealed by LDH zymography.
Beyond the cytoplasm, LDH also manifests in mitochondria, as evidenced by studies in various organisms. Mitochondrial L-lactate dehydrogenase (mL-LDH) facilitates the oxidation of L-lactate to pyruvate in the mitochondrial matrix, contributing to energy production. Cancer cells, which exhibit heightened glycolysis, may exploit mL-LDH to enhance oxidative phosphorylation.
At the molecular level, LDH is encoded by four genes: LDHA, LDHB, LDHC, and LDHD, yielding L-isomers of the enzyme. These genes provide instructions for assembling LDH-A and LDH-B subunits into tetrameric enzymes, with tissue-specific expression patterns. Additionally, two supplementary subunits, LDHC and LDHBx, contribute to LDH tetramer formation. Structurally, LDH comprises alpha helices and beta sheets, with a substrate-binding pocket housing catalytically essential amino acids. The M and H subunits maintain identical active site structures, but differences in flanking amino acids impart distinct kinetic properties. Notably, the H subunit, containing a glutamine residue instead of alanine found in the M subunit, exhibits faster substrate binding but reduced catalytic activity.
Unraveling the Functions of LDH
Lactate dehydrogenase (LDH) functions as an oxidoreductase enzyme, facilitating the reversible conversion of pyruvate to lactate using NADH. It plays a crucial role in anaerobic glucose metabolism when oxygen availability is limited. Under anaerobic or hypoxic conditions, disrupted oxidative phosphorylation prompts cells to rely on alternate metabolic pathways, leading to upregulation of LDH to meet energy demands. Lactate, a byproduct of this process, is transported to the liver via the bloodstream, where LDH facilitates its conversion back to pyruvate through the Cori cycle.
During exercise or in erythrocytes lacking mitochondria, LDH catalyzes pyruvate into lactic acid, regenerating NAD+ essential for glycolysis. However, anaerobic glycolysis yields only 2 ATP per glucose compared to 36 ATP from oxidative phosphorylation. LDH can also dehydrogenate 2-hydroxybutyrate, albeit less efficiently than lactate.
LDH's subunit composition varies among tissues, reflecting differences in metabolic rates and energy needs. Skeletal muscles release a significant portion of circulating lactate, absorbed mainly by the liver and kidneys for glucose synthesis. In the brain, lactate serves as an energy substrate, particularly during hyperlactatemia and physical exertion.
In cancer cells, LDH, particularly LDHA, functions differently, contributing to increased aerobic metabolism even in oxygen-rich environments, known as the Warburg effect. Cancer cells exploit anaerobic pathways to avoid oxidative stress and acquire metabolic intermediates for rapid proliferation.
Overall, LDH's diverse functions highlight its pivotal role in cellular metabolism, energy production, and pathological conditions like cancer, underscoring its significance as a therapeutic target and diagnostic marker.
LDH Testing
LDH assays gauge the enzyme's quantity in serum leaked from damaged tissues. LDH catalyzes L-lactate to pyruvate, with NAD+ as the hydrogen acceptor, measured spectrophotometrically at 340 nm by clinical labs. LDH activity is measurable in plasma, serum, tissues, cells, and culture mediums. Hemolysis during sample handling can falsely elevate LDH levels. Normal LDH ranges from 140 to 280 U/L but vary with age and sample type.
Various factors, including drugs and medications, affect LDH testing accuracy. High vitamin C levels may decrease LDH, while anesthetics, aspirin, and narcotics can elevate it. Elevated LDH levels are associated with liver, kidney, muscle, heart diseases, trauma, infections, cancer, and anemia.
LDH isozyme testing aids in assessing tissue damage severity and location. LDH comprises H and M subunits, synthesized tissue-specifically. Isozyme LDH-1 is heart-specific, while LDH-5 is liver-specific. Electrophoretic testing distinguishes LDH isozymes based on their migration patterns, providing insights into tissue damage severity and type.
Unveiling LDH in Pathophysiology
The quantification of LDH serves as a crucial clinical tool, reflecting tissue-specific pathology through its isozyme forms and widespread presence. Elevated LDH levels in serum indicate tissue damage, persisting for up to 7 days post-injury. LDH is a valuable marker for disease staging, prognosis monitoring, and treatment response evaluation. In conditions like acute myocardial infarction and liver injury, specific LDH isozymes remain elevated, aiding diagnosis and prognosis.
Effusion in serous body fluids elevates LDH, aiding in characterizing effusion types. In conditions like intracranial hemorrhage and malignancies, LDH levels surge, correlating with disease severity and metastatic potential. LDH is a key prognostic factor, particularly in cancers, indicating reduced survival rates in patients with high LDH levels. LDH serves as a therapeutic target in diseases like malaria and cancer, with inhibitors showing promise in selectively targeting pathogens or tumor cells.
LDH deficiency, though rare, manifests differently based on affected genes. LDHA gene mutations lead to skeletal muscle weakness and rhabdomyolysis, while LDHB gene mutations primarily affect cardiac muscle function without visible symptoms. Both mutations have implications in tumorigenesis, highlighting LDH's multifaceted role in health and disease.
Conclusion
In essence, LDH epitomizes the intricate interplay between cellular metabolism and clinical pathology, transcending its canonical role as a metabolic enzyme to emerge as a potent biomarker and therapeutic target. A comprehensive understanding of LDH's biochemical intricacies, clinical implications, and testing methodologies is imperative for unraveling its multifaceted role in health and disease. As research continues to unveil the enigmatic facets of LDH biology, novel diagnostic and therapeutic paradigms are poised to revolutionize disease management, heralding a new era in precision medicine.
References
- Zhou Y., et al. Current status and future perspectives of lactate dehydrogenase detection and medical implications: a review. Biosensors. 2022, 12(12): 1145.
- Farhana A., Lappin S.L. Biochemistry, lactate dehydrogenase. StatPearls. 2020.
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