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Aspartate transaminase

Aspartate transaminase (AST), also known as aspartate aminotransferase, is an enzyme that catalyzes the reversible interconversion of aspartate and α-ketoglutarate to oxaloacetate and glutamate, utilizing pyridoxal-5'-phosphate as a cofactor.^[1] This reaction plays a crucial role in amino acid metabolism, facilitating the redistribution of nitrogen groups and supporting gluconeogenesis and the tricarboxylic acid (TCA) cycle.^[2] AST is present in nearly all tissues but is particularly abundant in the liver, heart, skeletal muscle, kidneys, pancreas, brain, and erythrocytes.^[3] AST exists in two main isoforms: a cytosolic form (cAST) and a mitochondrial form (mAST), which share structural similarities, such as approximately 48% amino acid sequence homology in some species, and are both dimeric proteins requiring the pyridoxal phosphate cofactor for activity.^[2] The enzyme's structure enables it to function in both soluble cytoplasmic and membrane-bound mitochondrial compartments, with the mitochondrial isoform often predominant in hepatic cells.^[1] Physiologically, AST contributes to cellular energy production by linking amino acid catabolism to carbohydrate synthesis and fueling the TCA cycle, while also aiding in the detoxification of ammonia through glutamate formation.^[2] In clinical practice, serum AST levels are routinely measured via blood tests to evaluate liver health and detect cellular injury, as the enzyme is released into the bloodstream upon damage to tissues where it is concentrated.^[4] Normal AST concentrations in adults typically range from 0 to 35 units per liter (U/L), though values can vary slightly by age, sex, and laboratory standards, with newborns exhibiting higher ranges up to 140 U/L.^[3] Elevated AST levels, often exceeding 10 times the upper limit in acute cases, signal hepatocellular damage from conditions such as viral hepatitis, alcoholic liver disease, cirrhosis, or toxin exposure, and can also indicate non-hepatic issues like myocardial infarction, muscle trauma, or hemolysis.^[1] The AST/ALT ratio is a key diagnostic tool; a ratio greater than 2 suggests alcoholic liver injury, while a ratio below 1 is more indicative of viral hepatitis.^[3] Low AST levels are generally not clinically significant but may occur in conditions like vitamin B6 deficiency, advanced chronic kidney disease, or dialysis.^[3] AST testing is commonly included in liver function panels alongside alanine aminotransferase (ALT) for comprehensive assessment, with abnormal results prompting further investigations such as imaging or biopsies.^[4] Beyond diagnostics, AST's role in nitrogen metabolism has implications in therapeutic strategies, including targeting glutamine-dependent pathways in cancer treatment.^[2]

Biological Function

Role in Amino Acid Metabolism

Aspartate transaminase (AST), also known as aspartate aminotransferase, is a pyridoxal phosphate (PLP)-dependent transaminase enzyme classified under EC 2.6.1.1 that catalyzes the reversible transfer of the α-amino group from L-aspartate to α-ketoglutarate, yielding oxaloacetate and L-glutamate.^[5]^[6] The reaction proceeds as follows:

\text{L-aspartate} + \alpha\text{-ketoglutarate} \rightleftharpoons \text{oxaloacetate} + \text{L-glutamate}

^[7] This transamination reaction plays a central role in amino acid metabolism by facilitating the interconversion between amino acids and their corresponding keto acids, enabling the breakdown of aspartate during catabolism and its synthesis from oxaloacetate in anabolic processes.^[1] AST integrates into broader metabolic pathways through its products: oxaloacetate directly enters the citric acid cycle as a key intermediate, supporting energy production and carbon flux, while also serving as a precursor for gluconeogenesis via conversion to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase.^[8] Additionally, the glutamate produced contributes nitrogen to the urea cycle, where aspartate itself donates the second nitrogen atom for urea synthesis via argininosuccinate synthase, thus linking amino acid degradation to nitrogen excretion.^[9] Physiologically, AST is essential for amino acid degradation by removing amino groups from aspartate, allowing its carbon skeleton to fuel energy pathways, and for biosynthesis by reversing the process to generate non-essential amino acids.^[1] It also supports nitrogen shuttling between tissues, such as transferring amino groups from peripheral tissues to the liver for detoxification via the urea cycle, thereby maintaining nitrogen homeostasis.^[8] In serum, the half-life of AST activity for the cytosolic form is approximately 17 hours, influencing its detection in metabolic or pathological contexts.^[10]

Isoenzymes and Tissue Distribution

Aspartate transaminase (AST) exists in two distinct isoenzymes: the cytosolic form (cAST), encoded by the GOT1 gene, and the mitochondrial form (mAST), encoded by the GOT2 gene. These isoenzymes share high sequence similarity but differ in their subcellular localization and functional roles within the malate-aspartate shuttle. The GOT1 gene is located on chromosome 10q24.1-q25.1, while GOT2 resides on chromosome 16q22.1, reflecting their evolutionary conservation across prokaryotes and eukaryotes, where AST homologs facilitate essential amino acid transamination in diverse organisms.^[11] cAST is primarily expressed in the cytoplasm of cells and is found in high concentrations in the liver, heart, skeletal muscle, kidney, brain, and erythrocytes. Under normal physiological conditions, cAST accounts for the vast majority (>90%) of total serum AST activity, as it is more readily released into circulation from minor cellular perturbations.^[12] In contrast, mAST is localized to the mitochondrial matrix and is predominantly present in the liver, heart, and kidney, where it constitutes about 80% of the total AST activity within hepatic tissue. mAST contributes only a small proportion (typically <10%) to normal serum AST levels but has a notably longer half-life of approximately 87 hours compared to the shorter circulation time of cAST.^[8]^[13] Tissue distribution of AST activity varies significantly, with the highest levels observed in the liver and heart, reflecting their central roles in metabolism and energy production. Lower activity is noted in the pancreas and lungs, while moderate expression occurs in skeletal muscle and the brain. These patterns underscore the isoenzymes' contributions to tissue-specific amino acid homeostasis without significant isoform-specific tissue exclusivity.^[8]^[13]

Molecular Properties

Protein Structure

Aspartate transaminase (AST) is a homodimeric enzyme, with each subunit consisting of approximately 412 amino acids in the cytosolic isoform (cAST, UniProt P17174) and a molecular weight of about 46 kDa. The mitochondrial isoform (mAST, UniProt P00558) has an additional N-terminal targeting sequence of 25-30 residues, resulting in a mature form similar in size to cAST. Each subunit features two domains: a large domain (residues ~47-326) and a small domain (residues ~10-46 and ~327-412), connected by a flexible hinge loop that allows conformational changes between open and closed states during catalysis. The structure includes a central eight-stranded β-sheet flanked by α-helices, typical of the fold-type I PLP-dependent enzymes in the aspartate aminotransferase superfamily. The active site, located at the domain interface, binds the pyridoxal 5'-phosphate (PLP) cofactor via a Schiff base linkage to Lys258. The two isoforms share about 48% amino acid sequence identity and similar tertiary structures, enabling their function in distinct cellular compartments.^[14]^[15]

Catalytic Mechanism

Aspartate transaminase (AST), also known as aspartate aminotransferase, operates via a ping-pong bi-bi mechanism characteristic of PLP-dependent enzymes, where the enzyme alternates between pyridoxal 5'-phosphate (PLP)-bound and pyridoxamine 5'-phosphate (PMP)-bound forms during the two half-reactions of transamination.^[16] In this process, the amino group from L-aspartate is first transferred to PLP, releasing oxaloacetate, before the PMP form accepts an amino group from α-ketoglutarate to produce L-glutamate and regenerate PLP.^[16] This mechanism ensures sequential substrate binding and product release, minimizing unproductive complexes.^[17] The first half-reaction begins with the PLP cofactor forming an internal aldimine with Lys258 of the enzyme, positioning the enzyme in its open conformation for substrate entry.^[16] L-aspartate binds, initiating transaldimination: the substrate's amino group attacks the PLP C4' carbon, forming a geminal diamine intermediate that rearranges to an external aldimine.^[16] Deprotonation at the α-carbon by Lys258 then generates a quinonoid (carbanionic) intermediate, stabilized by protonation of the PLP pyridine nitrogen, which is rate-limiting with a rate constant of approximately 230 s⁻¹.^[16] This is followed by protonation to form a ketimine, hydrolysis through carbinolamine intermediates, and dissociation of oxaloacetate, yielding the PMP-bound enzyme with a net rate of 425 s⁻¹ for subsequent steps.^[16] In the second half-reaction, α-ketoglutarate binds to the PMP form, where the keto group attacks the PMP C4' carbon, forming a carbinolamine that dehydrates to an external imine (ketimine).^[16] Protonation at the α-carbon and deprotonation at C4' produce a quinonoid intermediate, followed by tautomerization to the internal aldimine and regeneration of the PLP form, with release of L-glutamate.^[16] The overall reaction, L-aspartate + α-ketoglutarate ⇌ oxaloacetate + L-glutamate, reflects this reversible ping-pong cycle.^[18] Kinetic parameters for human AST include a Michaelis constant (Km) of approximately 2.1 mM for L-aspartate and 0.25 mM for α-ketoglutarate, with an optimal pH around 7.5 where activity decreases by 50% at pH 7.0 or 8.0.^[19]^[20] The enzyme is inhibited by substrate analogs such as maleate, which binds to the PLP form and induces conformational changes, achieving up to 78% inhibition at 4 mM concentration.^[21]^[22] This catalytic mechanism is evolutionarily conserved across PLP-dependent transaminases in the aspartate aminotransferase superfamily, reflecting ancient adaptations for amino acid metabolism through shared intermediates and active-site architecture.^[23]

Clinical and Research Applications

Diagnostic Significance

Aspartate transaminase (AST), also known as serum glutamic oxaloacetic transaminase (SGOT), was first identified as a clinically relevant biomarker in the 1950s, with early reports by Karmen et al. in 1955 demonstrating elevated serum levels in patients with acute hepatitis and myocardial infarction using coupled enzyme reactions.^[24] De Ritis et al. further confirmed its elevation in viral hepatitis that same year, establishing its diagnostic potential for liver injury.^[24] Standardized assays for AST emerged in the 1970s through efforts like those of the International Federation of Clinical Chemistry (IFCC), which developed reference methods to ensure reproducibility across laboratories.^[8] In clinical practice, AST is measured primarily via spectrophotometric assays that quantify enzyme activity in serum or plasma. The standard method involves a coupled reaction where AST catalyzes the transfer of an amino group from aspartate to α-ketoglutarate, producing oxaloacetate, which is then reduced to malate by malate dehydrogenase in the presence of NADH; the decrease in NADH absorbance at 340 nm is monitored kinetically.^[25] These assays are automated in modern clinical laboratories using instruments like the Cobas analyzer, with results reported in international units per liter (IU/L).^[26] Normal serum AST reference ranges vary by laboratory, age, and sex, but typical values are 8–48 IU/L for adult males and 8–43 IU/L for adult females, with levels generally higher in males due to greater muscle mass.^[27] In children aged 1–13 years, ranges are broader, such as 8–60 IU/L for boys and 8–50 IU/L for girls, reflecting developmental differences.^[27] Factors like strenuous exercise, alcohol consumption, and obesity can transiently elevate AST levels by 20–50% above baseline, even in healthy individuals, necessitating consideration of recent activities when interpreting results.^[28] AST levels are often evaluated alongside alanine transaminase (ALT) to assess hepatocellular injury, where both enzymes are released from damaged liver cells and typically rise concurrently.^[28] An AST/ALT ratio greater than 2:1 is suggestive of alcoholic liver disease, as AST is disproportionately elevated due to its higher concentration in mitochondria and alcohol's preferential mitochondrial toxicity.^[29] In non-alcoholic hepatocellular damage, ALT often exceeds AST.^[28] Elevations in AST primarily result from the release of the enzyme from injured cells in tissues such as the liver, heart, and skeletal muscle, with serum levels peaking 24–48 hours after acute injury.^[30] The plasma half-life of AST is approximately 17 hours, which influences the timing and duration of elevations; for instance, levels return to normal faster after transient insults compared to enzymes with longer half-lives like ALT (about 47 hours).^[8]^[28] This kinetic profile makes AST useful in routine monitoring of liver function panels for early detection of cellular damage.^[30]

Associations with Specific Diseases

Aspartate transaminase (AST) levels are frequently elevated in various liver diseases, serving as a marker for hepatocellular injury. In viral hepatitis, such as hepatitis B and C, and autoimmune hepatitis, AST elevations often parallel alanine aminotransferase (ALT) increases, reflecting acute or chronic inflammation.^[31] In cirrhosis, particularly alcohol-related, an AST/ALT ratio greater than 2 is a characteristic pattern indicative of mitochondrial damage from ethanol toxicity, correlating with disease progression and fibrosis severity.^[32] Cholestasis also leads to AST rises, though typically milder than in hepatocellular disorders, and the enzyme's levels can predict outcomes like hepatic decompensation in advanced cases.^[33] In cardiac conditions, AST peaks 24–36 hours after myocardial infarction, often alongside creatine kinase-MB, due to release from damaged cardiomyocytes, and its magnitude correlates with infarct size.^[8] An elevated AST/ALT ratio in acute myocardial infarction, especially ST-segment elevation types, is associated with worse short-term prognosis, including recurrent events and heart failure.^[34] In chronic heart failure, higher AST levels independently predict adverse outcomes, such as hospitalization and mortality, reflecting ongoing cardiac stress and congestion-related liver involvement.^[35] Narrative reviews indicate AST activity's association with cardiovascular disease risk, showing a U-shaped relationship where both low and high levels predict ischemic events and mortality in at-risk populations.^[8] AST elevations occur in non-hepatic conditions like muscle disorders, including rhabdomyolysis, where levels can exceed those in severe liver injury due to release from skeletal muscle, paralleling creatine phosphokinase declines during recovery.^[36] Acute kidney injury, often secondary to rhabdomyolysis, shows AST increases from myoglobinuric tubular damage, with enzyme patterns aiding differentiation from primary renal causes.^[37] Hemolysis elevates AST through leakage from erythrocytes, which contain the enzyme, contributing to spurious results in hemolytic anemias. Conversely, low AST levels are observed in vitamin B6 deficiency, as the cofactor pyridoxal phosphate is essential for AST activity, leading to reduced enzyme function and potential neurological complications.^[27] Recent studies highlight AST's role in emerging infectious and systemic diseases. In COVID-19, AST elevations occurred in up to 53% of cases, most commonly among liver enzyme abnormalities, and were linked to disease severity, longer hospital stays, and higher mortality risk, independent of direct viral liver tropism.^[38] In the brain, AST contributes to aspartate production, an excitatory neurotransmitter involved in neurotransmission; disruptions in this pathway are implicated in neurodegeneration, with 2025 reviews emphasizing altered aspartate metabolism in conditions like Alzheimer's disease.^[39] Genetic variants in AST-related genes, particularly bi-allelic mutations in GOT2 encoding the mitochondrial isoform, cause rare deficiencies leading to malate-aspartate shuttle dysfunction. These result in neurodevelopmental disorders, epileptic encephalopathy, and myelination abnormalities, often presenting in infancy with treatable responses to pyruvate supplementation.^[40]

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