alanine transaminase

alanine transaminase is a pivotal pyridoxal phosphate-dependent transferase that catalyzes a key reaction in amino acid metabolism. It is found in the cytosol of cells throughout the body, with particularly high concentrations in the liver. The enzyme's activity is a critical biomarker in clinical medicine for assessing hepatocellular health.

Function and reaction mechanism

The primary function of this enzyme is to reversibly transfer an amino group from the amino acid alanine to the alpha-ketoglutarate molecule. This transamination reaction yields pyruvate and the amino acid glutamate, linking carbohydrate and nitrogen metabolic pathways. The reaction is central to the glucose-alanine cycle, which facilitates nitrogen transport from muscle tissue to the liver. The mechanism relies on the coenzyme pyridoxal phosphate, which forms a Schiff base intermediate with the substrate. This process is analogous to reactions catalyzed by other aminotransferases like aspartate transaminase.

Clinical significance

Serum levels of this enzyme are a cornerstone of liver function tests and are routinely measured in panels such as the Comprehensive Metabolic Panel. Elevated levels are a hallmark of hepatocellular injury, as seen in conditions like viral hepatitis, alcoholic liver disease, and non-alcoholic steatohepatitis. It is also used to monitor potential hepatotoxicity caused by medications like isoniazid and statins. While highly sensitive for liver damage, levels can also rise in other conditions, including celiac disease, muscular dystrophy, and severe burns. The ratio of this enzyme to aspartate transaminase can aid in differentiating causes of jaundice, such as distinguishing between viral hepatitis and alcoholic hepatitis.

Measurement and units

Activity is measured in international units per liter (U/L) using automated analyzers in clinical laboratories like those following Clinical Laboratory Improvement Amendments standards. The most common assay method is the International Federation of Clinical Chemistry and Laboratory Medicine recommended procedure, which monitors the rate of NADH oxidation in a coupled reaction with lactate dehydrogenase. Reference intervals vary by laboratory and population but are typically higher in males than females. Institutions like the Mayo Clinic and Cleveland Clinic have established specific reference ranges. Results are interpreted in the context of other tests like alkaline phosphatase and bilirubin.

Genetics and isoforms

In humans, the enzyme is encoded by two distinct genes: GPT1 and GPT2, located on chromosomes 8q24.3 and 16q12.1, respectively. The GPT1 gene product is the predominant isoform expressed in the liver and kidneys, while GPT2 is primarily found in mitochondria of tissues like muscle and brain. Polymorphisms in these genes, studied in projects like the 1000 Genomes Project, can influence baseline serum activity. Research from the Broad Institute has investigated the role of the GPT2 isoform in certain metabolic disorders.

Regulation and inhibitors

Hepatic expression is regulated by hormones including glucocorticoids and insulin, as well as by dietary protein intake. The enzyme's activity can be inhibited by compounds that interact with the pyridoxal phosphate cofactor. Notable inhibitors include the antituberculosis drug cycloserine and the neurotoxin beta-cyano-L-alanine. Endogenous regulation occurs through substrate availability and product inhibition by glutamate. Research into specific inhibitors is ongoing in institutions like the National Institutes of Health for potential therapeutic applications in metabolic diseases. Category:Enzymes Category:EC 2.6.1