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Transamination

Transamination is a fundamental biochemical process in which an amino group (–NH₂) is reversibly transferred from an amino acid to an α-keto acid (or oxoacid), producing a new amino acid and a corresponding new α-keto acid.^[1]^[2] This reaction, which does not involve the net removal of the amino group, is catalyzed by a family of enzymes called aminotransferases (also known as transaminases), such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and requires pyridoxal 5'-phosphate (PLP), the active form of vitamin B₆, as a coenzyme.^[1]^[2] Transamination plays a central role in amino acid metabolism by facilitating the interconversion of amino acids and the redistribution of nitrogen within cells, typically using α-ketoglutarate as the primary keto acid acceptor to form glutamate.^[1]^[2] The mechanism of transamination proceeds in two half-reactions mediated by the PLP-bound enzyme.^[1] In the first step, the amino acid donates its amino group to PLP, forming a ketimine intermediate that releases the corresponding α-keto acid; this is followed by hydrolysis of the ketimine to regenerate PLP and produce the new amino acid from the acceptor keto acid.^[1]^[2] Most amino acids participate in transamination, with notable exceptions including lysine, proline, and threonine, which lack the appropriate structural features for the reaction.^[2] Common examples include the conversion of alanine to pyruvate (catalyzed by ALT) and aspartate to oxaloacetate (catalyzed by AST), often linking amino acid catabolism to central pathways like the citric acid cycle and gluconeogenesis.^[1]^[2] Biologically, transamination is essential for the synthesis of non-essential amino acids, the initial step in amino acid degradation by separating the carbon skeleton from the amino group, and the overall nitrogen balance in organisms.^[2] It enables the recycling of amino groups into glutamate, which serves as a nitrogen donor for other amino acids or for urea synthesis in the urea cycle, preventing toxic ammonia accumulation.^[2] Aminotransferases are ubiquitous in eukaryotic and prokaryotic cells, with AST present in both cytosolic and mitochondrial forms across tissues like the liver, heart, and muscle, while ALT is predominantly cytosolic in the liver.^[1] Clinically, elevated serum levels of AST and ALT are key diagnostic markers for liver damage, such as in viral hepatitis, cirrhosis, or myocardial infarction, where AST/ALT ratios help differentiate conditions (e.g., AST exceeding ALT in alcoholic liver disease).^[1]

Fundamentals

Definition and Process Overview

Transamination is the reversible transfer of an amino group (-NH₂) from an amino acid to an α-keto acid, yielding a new amino acid and a new α-keto acid.^[1] This biochemical reaction enables the interchange of amino and keto functionalities between molecules, serving as a fundamental process in nitrogen metabolism.^[3] The process is catalyzed primarily by transaminases, a class of enzymes that facilitate this group transfer.^[4] The general reaction scheme for transamination can be expressed as follows:

\text{Amino acid}_1 + \alpha\text{-keto acid}_2 \rightleftharpoons \alpha\text{-keto acid}_1 + \text{Amino acid}_2

This balanced equation illustrates the stoichiometric exchange without net consumption or production of amino or keto groups.^[5] A representative example involves aspartate and α-ketoglutarate, which react to form oxaloacetate and glutamate, highlighting the reaction's role in linking amino acids to key metabolic intermediates.^[5] Transamination is essential in biology as it allows for the interconversion of amino acids, enabling cells to synthesize non-essential amino acids from precursors and to redistribute nitrogen efficiently.^[6] By shuttling nitrogen groups between amino acids and keto acids, it supports amino acid homeostasis and integrates nitrogen metabolism with carbohydrate and energy pathways, all without necessitating the net breakdown of proteins.^[7] This mechanism is particularly vital in tissues like the liver and muscle, where it coordinates the flow of nitrogen for biosynthesis and detoxification.^[8]

Historical Development

The concept of transamination emerged from early studies on amino acid metabolism using isotopic tracers. In 1937, Rudolf Schoenheimer and David Rittenberg demonstrated, through experiments with heavy nitrogen (¹⁵N)-labeled compounds in rats, that amino groups could be rapidly exchanged between different amino acids and other nitrogenous compounds, indicating dynamic intermediary metabolism beyond simple protein synthesis and breakdown.^[9] Their work, building on prior isotopic techniques introduced in 1935, provided the first indirect evidence for amino group transfer processes, though the enzymatic nature remained unclear at the time.^[9] The enzymatic basis of transamination was established shortly thereafter by Alexander E. Braunstein and Maria G. Kritzman. In 1937, working with pigeon breast muscle extracts, they observed the reversible transfer of amino groups from L-aspartate or L-alanine to α-ketoglutarate, forming oxaloacetate or pyruvate and glutamate, respectively—a process they termed "transamination" to distinguish it from decarboxylation or deamination.^[10] This discovery, confirmed in animal tissues during the early 1940s, highlighted transamination as a widespread metabolic reaction linking carbohydrate and amino acid pathways, with Braunstein's group purifying crude enzyme preparations and demonstrating its occurrence in multiple organs by 1946.^[11] Subsequent decades saw key advances in isolating and characterizing the enzymes involved. In the 1950s, researchers achieved significant purification of transaminases, such as the tyrosine-α-ketoglutarate transaminase from rat liver in 1956, enabling detailed kinetic studies and confirmation of their specificity. In the late 1940s, pyridoxal 5'-phosphate (PLP), the active form of vitamin B₆, was identified as the essential cofactor; spectroscopic and chemical studies in the 1950s confirmed PLP forming a Schiff base with the enzyme's lysine residue, facilitating the ping-pong mechanism of amino group transfer. Structural insights deepened in the 1980s with X-ray crystallography, including the three-dimensional structure of cytosolic aspartate aminotransferase from chicken heart determined in 1982 at 3.2 Å resolution, revealing the dimeric architecture and active-site geometry.^[12] Initially viewed as a straightforward amino group exchange, understanding of transamination evolved to recognize it as a pivotal hub in nitrogen homeostasis and intermediary metabolism, integrating amino acid synthesis, gluconeogenesis, and neurotransmitter production across species.^[10] This shift was driven by the cumulative milestones, transforming transamination from an obscure reaction into a cornerstone of biochemistry by the late 20th century.

Biochemical Mechanism

Enzymatic Transamination

Enzymatic transamination is catalyzed by transaminases, which are pyridoxal 5'-phosphate (PLP)-dependent enzymes that facilitate the reversible transfer of an amino group from an amino acid donor to a keto acid acceptor.^[4] The process follows a ping-pong bi-bi kinetic mechanism, characterized by two sequential half-reactions where the enzyme alternates between PLP-bound and pyridoxamine 5'-phosphate (PMP)-bound forms, with the first substrate (amino acid donor) binding and reacting before release of the first product (keto acid), followed by binding of the second substrate (keto acid acceptor). This bipartite nature ensures efficient group transfer without direct interaction between the two substrates on the enzyme.^[13] In the first half-reaction, the amino acid donor binds to the enzyme's active site, where PLP is initially linked to a lysine residue as an internal aldimine. Step 1 involves transaldimination, forming an external aldimine intermediate between PLP and the amino acid substrate, often via a transient geminal diamine.^[14] Step 2 proceeds with abstraction of the α-proton from the external aldimine by a lysine residue, generating a quinonoid intermediate—a carbanionic species stabilized by resonance with the PLP ring—followed by protonation at the C4' position of PLP, leading to formation of a ketimine intermediate and subsequent release of the keto acid product, leaving the enzyme in its PMP-bound form.^[4] The second half-reaction involves binding of the keto acid acceptor to the PMP-bound enzyme, initiating a reverse process that regenerates the PLP form. The amino group from PMP transfers to the keto acid, forming a carbinolamine intermediate that dehydrates to an external aldimine, followed by α-protonation to yield the new amino acid product, which is then released, restoring the internal aldimine of PLP-enzyme.^[13] This step completes the cycle, enabling the enzyme to catalyze multiple turnovers. The full PLP-mediated cycle can be represented as follows, using aspartate and α-ketoglutarate as an example pair:

\begin{align*} &\text{Enzyme-PLP (internal aldimine)} + \text{L-aspartate} \rightleftharpoons \text{Enzyme-PLP-L-aspartate (external aldimine)} \\ &\quad \rightleftharpoons \text{Enzyme-PLP-L-aspartate (quinonoid)} \rightleftharpoons \text{Enzyme-PMP + oxaloacetate (keto acid)} \\ &\text{Enzyme-PMP + α-ketoglutarate} \rightleftharpoons \text{Enzyme-PMP-α-ketoglutarate (external aldimine)} \\ &\quad \rightleftharpoons \text{Enzyme-PLP + L-glutamate (new amino acid)} \end{align*}

This scheme highlights the key intermediates: external aldimine, quinonoid, and ketimine, with the overall reaction being L-aspartate + α-ketoglutarate ⇌ oxaloacetate + L-glutamate.^[14] The reaction is thermodynamically favorable for many substrate pairs due to equilibrium constants near 1, resulting in approximately 50% conversion yields under standard conditions, which allows reversibility in metabolic contexts.^[15]

Non-Enzymatic Transamination

Non-enzymatic transamination refers to the transfer of an amino group between an amino acid and a keto acid without the involvement of enzymes, typically proceeding through a direct nucleophilic attack by the amine on the carbonyl group of the keto acid. This forms a carbinolamine intermediate that dehydrates to an imine, followed by tautomerization via deprotonation to an azomethine ylide and subsequent hydrolysis to yield the exchanged products. The reaction often requires acidic conditions to facilitate imine formation and decarboxylation, as demonstrated in studies of amino acid-keto acid pairs refluxed in water.^[16]^[17] These reactions occur under harsh in vitro conditions, such as elevated temperatures (e.g., 85–100°C) or geochemical environments like acidic hydrothermal vents, and exhibit rate constants orders of magnitude lower than their enzymatic counterparts—for instance, an uncatalyzed rate of approximately $2.9 \times 10^{-7} s^{-1} at neutral pH and room temperature, corresponding to half-lives of weeks to months.^[17] Yields are typically low (1–12%) without catalysts, reflecting the thermodynamic barriers to imine tautomerization and hydrolysis. In contrast to enzymatic processes, which achieve near-diffusion-limited rates, non-enzymatic transamination's inefficiency underscores its limited utility in biological systems.^[16] A key example arises in prebiotic chemistry, where non-enzymatic transamination between glycine and glyoxylate contributes to pathways forming serine precursors, such as through coupled β-elimination and amino group transfer under mild aqueous conditions (e.g., 50–70°C, pH 6–8). This reaction, observed as early as 1960 and revisited in modern protometabolic studies, highlights its potential role in early Earth molecular evolution by generating α-keto acids and amino acids from simple precursors.^[18]^[19] While non-enzymatic transamination plays a minor role in vivo—potentially as trace background reactions in cellular environments under stress where enzymatic control is disrupted—it gains prominence in industrial applications for amino acid synthesis via metal-ion catalysis (e.g., Cu²⁺ or Ni²⁺ enhancing rates up to 2700-fold) and in astrobiology for modeling prebiotic networks. However, inherent limitations include poor substrate specificity, leading to side products like decarboxylated byproducts, and low overall yields (often <10% without aids), restricting its practical scalability.^[20]^[21]

Enzymes and Molecular Details

Structure and Classification of Transaminases

Transaminases, also known as aminotransferases, are classified within the Enzyme Commission (EC) group 2.6.1.x, which encompasses enzymes catalyzing the transfer of an amino group from an amino acid to a keto acid. This classification is based on substrate specificity, with the fourth digit indicating particular reactions, such as EC 2.6.1.1 for aspartate transaminase and EC 2.6.1.2 for alanine transaminase. Structurally, transaminases belong to two primary families among pyridoxal 5'-phosphate (PLP)-dependent enzymes: fold type I, also known as the aspartate aminotransferase (AAT) fold, which predominates in most α-transaminases, and fold type IV, the D-amino acid aminotransferase fold, characteristic of enzymes acting on D-amino acids and certain branched-chain substrates.^[22]^[4] These enzymes typically form homodimeric or tetrameric quaternary structures, with each subunit comprising two distinct domains: a large domain rich in α-helices and a smaller domain that contributes to the PLP-binding pocket. The active site is conserved across families and features a lysine residue that forms a covalent Schiff base with the PLP cofactor's aldehyde group, facilitating the transamination reaction. For instance, in fold type I enzymes like aspartate transaminase, the homodimeric structure positions the active sites at the subunit interface, enhancing stability and substrate access.^[23]^[24]^[4] Prominent examples include alanine transaminase (ALT, EC 2.6.1.2), which catalyzes the reversible transfer of the amino group from L-alanine to 2-oxoglutarate, producing pyruvate and L-glutamate, and is essential in liver metabolism. Aspartate transaminase (AST, EC 2.6.1.1) transfers the amino group from L-aspartate to 2-oxoglutarate, yielding oxaloacetate and L-glutamate, playing a key role in the malate-aspartate shuttle. Both enzymes exemplify fold type I architecture.^[25]^[26]^[4] Transaminases are evolutionarily ancient, with origins traceable to the last universal common ancestor (LUCA), and are ubiquitous across prokaryotes and eukaryotes, reflecting their fundamental role in amino acid metabolism. In humans, gene families encode isoforms adapted to subcellular localization, such as the cytosolic GOT1 and mitochondrial GOT2 for AST, which share high sequence similarity but differ in targeting signals. Similarly, ALT exists as cytosolic ALT1 (GPT1) and mitochondrial ALT2 (GPT2) isoforms, enabling compartmentalized metabolic functions.^[4]^[27]^[28]

Cofactors and Reaction Kinetics

Transamination reactions are catalyzed by pyridoxal 5'-phosphate (PLP)-dependent enzymes known as transaminases, where PLP, the active form of vitamin B6, serves as the essential cofactor. PLP binds covalently to a conserved lysine residue in the enzyme's active site, forming an internal aldimine (Schiff base) that facilitates the transfer of amino groups between substrates.^[29] This Schiff base linkage positions the cofactor for interaction with amino acid substrates, enabling the reversible ping-pong mechanism characteristic of these reactions.^[30] The chemistry of PLP in transamination involves key tautomerization steps that stabilize reactive intermediates and drive group transfer. Upon binding of an amino acid donor, the external aldimine forms, followed by deprotonation at the α-carbon to generate a quinonoid intermediate; subsequent reprotonation and tautomerization yield the ketimine, which hydrolyzes to release the α-keto acid product and form enzyme-bound pyridoxamine 5'-phosphate (PMP).^[31] These tautomerization events lower the energy barrier for proton abstraction and transfer, making PLP uniquely suited for amino group shuttling. Deficiency in vitamin B6 impairs PLP availability, leading to reduced transaminase activity; for instance, in pyridoxine-deficient models, leucine transaminase activity decreases significantly in tissues like kidney, contributing to metabolic disruptions in B6-related disorders such as peripheral neuropathy and hyperoxaluria due to defective glyoxylate transamination.^[32]^[33]^[34] The kinetics of transamination follow Michaelis-Menten behavior, with rate parameters reflecting enzyme-substrate interactions. Typical Km values for amino acid substrates range from 0.1 to 10 mM, as seen in aspartate aminotransferase (Km ≈ 6.7 mM for L-aspartate and ≈ 0.3 mM for α-ketoglutarate) and branched-chain amino acid transaminases (Km < 0.5 mM for leucine and 0.6–3 mM for α-ketoglutarate).^[35] Vmax values vary with substrate specificity, often higher for physiological pairs like L-aspartate/oxaloacetate compared to non-native substrates, underscoring the role of active-site residues in catalytic efficiency. Transaminases exhibit competitive inhibition by PLP analogs such as aminooxyacetate, which forms a stable oxime with the cofactor's aldehyde, blocking Schiff base formation and reducing activity by over 90% at micromolar concentrations.^[36] Optimal pH for most transaminases falls between 7 and 8, with aspartate aminotransferase peaking at pH 7.4–7.5 and others like alanine aminotransferase at pH 7.5–8.5, reflecting the protonation state required for PLP tautomerization and substrate binding.^[37]^[38]^[39] Isotope effects provide insights into mechanistic details, particularly rate-limiting steps involving proton transfer. Deuterium substitution at the α-carbon of substrates like tyrosine or γ-aminobutyric acid yields kinetic isotope effects (KIE ≈ 2–4), indicating that C-H bond cleavage is partially or fully rate-limiting in the quinonoid intermediate formation during transamination.^[40]^[41] Solvent deuterium isotope effects (D2O vs. H2O) further confirm proton abstraction as a key bottleneck, with KIE values supporting the involvement of enzyme-bound bases in facilitating these transfers.^[42]

Physiological and Clinical Roles

Role in Amino Acid Metabolism

Transamination serves as a pivotal process in the biosynthesis of non-essential amino acids, enabling the transfer of amino groups from glutamate to α-keto acids derived from glycolysis and the tricarboxylic acid cycle (TCAC). For example, pyruvate, a glycolytic intermediate, is converted to alanine through transamination with glutamate, a reaction that supports the production of alanine as a key carrier of ammonia from peripheral tissues to the liver. Similarly, oxaloacetate from the TCAC is transaminated to form aspartate, which is essential for various biosynthetic pathways. This mechanism allows cells to synthesize amino acids on demand without relying solely on dietary intake, maintaining nitrogen balance under varying nutritional conditions.^[43] In amino acid catabolism, transamination initiates the degradation process by removing amino groups from excess amino acids, primarily funneling nitrogen into glutamate via enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Glutamate then acts as a central nitrogen donor, channeling excess nitrogen into glutamine for transport to the liver, where it links to the urea cycle for detoxification and excretion. This step is crucial for preventing ammonia toxicity while providing carbon skeletons from the resulting keto acids for energy production or gluconeogenesis. Transamination is particularly prominent in the initial breakdown of glucogenic and ketogenic amino acids, ensuring efficient nutrient utilization during fasting or high-protein diets.^[44] Transamination integrates into specific pathways like branched-chain amino acid (BCAA) metabolism, where leucine, isoleucine, and valine undergo transamination in skeletal muscle to form branched-chain α-keto acids, dispersing nitrogen according to tissue needs and supporting energy demands. In neurotransmitter synthesis, transamination facilitates the interconversion between glutamate and α-ketoglutarate in the brain, enabling rapid production of excitatory neurotransmitters essential for synaptic function. These reactions are catalyzed by pyridoxal phosphate-dependent transaminases.^[45]^[46] The regulation of transamination involves allosteric control by substrates and products, where high glutamate levels promote activity while keto acid accumulation can inhibit it, fine-tuning the process to metabolic demands. Hormonal signals, such as glucagon, upregulate transaminase expression and activity in the liver during fasting, enhancing amino acid catabolism to provide gluconeogenic substrates and maintain blood glucose levels. Organ-specific roles further highlight its physiological integration: in the liver and kidneys, transamination supports systemic nitrogen homeostasis and urea production, whereas in the brain, it addresses local requirements for amino acid interconversions in neuronal metabolism. Recent Mendelian randomization studies as of 2025 suggest a potential causal relationship between elevated AST levels and increased risk of hypertension, expanding the physiological implications beyond liver function.^[1]^[47]^[44]^[46]^[48]

Diagnostic and Pathological Significance

Transaminases, particularly alanine aminotransferase (ALT) and aspartate aminotransferase (AST), serve as critical biomarkers in clinical diagnostics due to their elevation in response to liver injury. In healthy adults, normal serum ALT levels range from 7 to 56 U/L, while AST levels typically fall between 8 and 48 U/L.^[49]^[50] Elevated ALT and AST levels indicate hepatocyte damage and inflammation, commonly observed in conditions such as viral hepatitis and non-alcoholic fatty liver disease (NAFLD). For example, in NAFLD, higher ALT/AST ratios are associated with increased risk and severity of liver fibrosis.^[51]^[52] The AST/ALT ratio further aids in distinguishing etiologies; a ratio exceeding 2:1 is suggestive of alcoholic liver disease, whereas viral hepatitis often presents with ALT predominance.^[53]^[54] Pathological conditions involving transaminases are often linked to disruptions in their function or regulation. Genetic defects, such as rare mutations in the GOT1 gene encoding cytosolic AST, can lead to atypical presentations like macro-AST but are uncommon and typically do not cause overt deficiency syndromes.^[55] Vitamin B6 (pyridoxine) deficiency, which impairs transamination by reducing pyridoxal phosphate cofactor availability, can result in peripheral neuropathy due to disrupted amino acid metabolism.^[56]^[57] Such deficiencies may manifest as elevated or altered transaminase activity, highlighting the enzyme's sensitivity to cofactor status.^[58] In therapeutics, transaminases represent targets for modulating cancer metabolism, particularly in tumors reliant on glutamine via enzymes like GOT1. Inhibitors of glutamine-utilizing transaminases have shown promise as vulnerabilities in acute myeloid leukemia, disrupting aspartate production essential for nucleotide synthesis.^[59]^[60] Conversely, transaminases play a key role in detecting drug-induced liver injury (DILI), where their elevation signals hepatocellular toxicity from medications like isoniazid or acetaminophen, prompting discontinuation to prevent progression.^[61]^[62] Recent advances post-2020 have illuminated transaminases' involvement in emerging pathologies, including COVID-19-associated liver effects. Elevations in ALT and AST occur in 14% to 53% of COVID-19 patients, potentially due to direct viral impact, cytokine storm, or treatment-related factors, with higher levels correlating to disease severity.^[63]^[64] Additionally, gut microbiome dysbiosis influences transaminase activity; microbiome-targeted therapies, such as probiotics, have been shown to significantly lower ALT levels in NAFLD, underscoring the gut-liver axis in modulating enzyme expression and hepatic inflammation. As of 2025, the clinical utility of aminotransferases continues to evolve, with redefined thresholds accounting for age, gender, and metabolic risks, alongside integration with non-invasive tests and AI-driven algorithms to improve early detection and management of chronic liver diseases.^[65]^[66]^[67]

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ALT and AST are metabolic enzymes and the elevated levels of ALT and AST in the blood are indicative of hepatocyte necrosis and inflammation. The rise of AST is ...
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Aug 26, 2024 · A higher ALT/AST ratio was independently associated with a significantly higher risk of NAFLD and liver fibrosis within American cohorts.
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AST/ALT ratios below 1.0 are also typical of chronic viral hepatitis (e.g. hepatitis B and C), however ratios slightly above 1.0 may be found in chronic viral ...
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Jul 15, 2017 · We found a genetic variant in the GOT1 gene associated with macro-AST. Genetic testing for this variant may aid diagnosis of macro-AST.Missing: deficiency | Show results with:deficiency
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... Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. ... Targeting glutamine metabolism in breast cancer with ...
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Sep 10, 2024 · Drug-induced hepatotoxicity is an acute or chronic liver injury secondary to drugs or herbal compounds. It is difficult to diagnose.Introduction · Histopathology · History and Physical · Evaluation
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It is imperative that upon development of DILI the culprit drug be discontinued, especially in the presence of elevated transaminases (aspartate ...
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Transaminases and bilirubin levels were high in a significant majority of patients; however, the exact cause of liver damage is not entirely clear.
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