A synthetase is an enzyme that joins, or ligates, two smaller molecules to create a new, larger one. As biological catalysts, these proteins build the complex molecules necessary for cellular structure and function. By facilitating the bonding of separate molecules, synthetases help build everything from proteins to genetic material. This catalytic function allows life-sustaining reactions to occur at a pace compatible with the needs of the organism, as the construction of biological molecules would otherwise be too slow to support life.
The Role of Energy in Synthesis
A feature of all synthetases is their requirement for a direct energy input. The synthesis reactions they catalyze are energetically unfavorable and will not happen spontaneously. To overcome this barrier, synthetases harness chemical energy from high-energy molecules, most commonly Adenosine Triphosphate (ATP), the cell’s primary energy currency.
The process begins when the synthetase binds to its specific substrates and an ATP molecule. The enzyme then facilitates the hydrolysis of ATP, breaking a high-energy phosphate bond. This breakage releases energy that the enzyme uses to form a new chemical bond between the two substrates.
This coupling of ATP hydrolysis to the synthesis reaction is a principle in biochemistry. Think of it like using a battery to power a machine; the energy from ATP is necessary to make the synthetase enzyme perform its work of building something new. Once the new, larger molecule is formed, it is released from the enzyme, which is then free to catalyze the same reaction again.
Distinguishing Synthetase from Synthase
A common point of confusion is the difference between a “synthetase” and a “synthase,” as both names imply a role in synthesis. The distinction lies in their use of energy. According to the International Union of Biochemistry and Molecular Biology (IUBMB), the term synthetase is synonymous with ligase (Enzyme Class EC 6), which are enzymes that join two molecules using energy from a molecule like ATP.
In contrast, the term synthase is used for enzymes that catalyze synthesis reactions without direct energy input from ATP hydrolysis. These enzymes, often classified as lyases (Enzyme Class EC 4), use other chemical mechanisms. A classic example is ATP synthase, which produces ATP rather than consuming it.
The official nomenclature now recommends using “ligase” for enzymes traditionally called synthetases to make the distinction clearer. For example, an enzyme that joins an amino acid to a transfer RNA molecule using ATP is called an aminoacyl-tRNA ligase. However, the name aminoacyl-tRNA synthetase is still widely used and accepted.
Key Examples of Synthetases in Biology
One important group of these enzymes is the aminoacyl-tRNA synthetases (aaRS). These enzymes attach the correct amino acid to its corresponding transfer RNA (tRNA) molecule. This is a step in protein synthesis, ensuring the genetic code is accurately translated into the correct sequence of amino acids.
The precision of aminoacyl-tRNA synthetases is high. Each of the 20 standard amino acids has a dedicated synthetase that recognizes it and the correct set of tRNA molecules. This fidelity establishes the rules of the genetic code. If the wrong amino acid is attached to a tRNA, it can be incorporated into a protein, potentially leading to a non-functional product.
Another example is glutamine synthetase, which has a role in nitrogen metabolism. This enzyme catalyzes the formation of the amino acid glutamine from glutamate and ammonia in a reaction powered by ATP. This process is important for assimilating ammonia, which can be toxic at high levels. It also provides glutamine as a nitrogen donor for synthesizing other amino acids and nucleotides.
Synthetases in Health and Disease
Malfunctions in synthetase enzymes can have consequences for human health. Genetic mutations in the genes that code for synthetases can lead to various diseases. For instance, mutations affecting aminoacyl-tRNA synthetases are linked to inherited disorders that impact the nervous system, such as Charcot-Marie-Tooth disease. These conditions can arise even if the mutation doesn’t stop the enzyme’s main job, suggesting these proteins have other functions.
Recessive mutations in these same genes can cause severe multi-system disorders affecting the brain, liver, and lungs. Beyond genetic conditions, some autoimmune diseases, like anti-synthetase syndrome, involve the body producing antibodies that mistakenly attack its own synthetase enzymes.
The integral role of these enzymes in cell survival makes them attractive targets for drug development. Structural differences between bacterial and human synthetases allow for drugs that block the bacterial enzyme without harming the patient. The antibiotic mupirocin, for example, inhibits a bacterial aminoacyl-tRNA synthetase, stopping protein production and halting the infection. This principle is also being explored for new anticancer and antimalarial agents.