What is Citrate Synthase?

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  • Written By: Greg Caramenico
  • Edited By: Daniel Lindley
  • Last Modified Date: 20 October 2019
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The enzyme citrate synthase catalyzes the first step in a cellular metabolic process called the citric acid cycle. This process occurs in the majority of animal, plant, and bacterial cells, producing cellular energy for life, in the form of a molecule called ATP. The first step of this chain reaction uses the products of sugar metabolism to produce a substance called citrate, which is then further processed to yield energy. Like many enzymes, citrate synthase must first bind to a specific molecule, its substrate, before becoming chemically active.

Citrate synthase is produced in almost every cell type. It is the catalyst that initiates the first step of the basic metabolic reaction known as the citric acid cycle or the Krebs cycle, which occurs in all organisms that require oxygen for metabolism. The citric acid cycle produces ATP, a molecule used to fuel the basic processes of living cells, like respiration and reproduction. Citrate synthase is the first enzyme in the long chain of catalysts for the Krebs cycle, and the amount produced regulates the rate at which the entire cycle can proceed.


Like all enzymes, citrate synthase has a specific protein structure that enables it to catalyze reactions. It exists in the body in two separate states based on its conformation or shape: an active and inactive variety. During glycolysis, the sugar glucose, derived from food, has been metabolized into various chemicals, including two molecules of acetate that help initiate the Krebs cycle. When bound by a molecule of oxaloacetate, citrate synthase changes its conformation and opens a region on its surface to which the acetyl-CoA binds.

The mechanism of citrate synthase requires activation, which occurs when it binds to a compound called its substrate, in this case oxaloacetate, in a process called an induced fit. The inactive conformation of citrate synthase is known as its open form. Like other proteins, this enzyme is made up of many molecules of amino acids. When it binds to oxaloacetate, the shape is changed as certain amino acids are linked together, closing up and forming a kind of circle around the substrate. This closed form is the activation shape that enables the citric acid cycle to proceed.

Once the enzyme has bound to acetyl-CoA, it attaches a portion of the acetyl molecules to oxaloacetate, while at the same time chemically removing the CoA section. The transferred part, an acetate molecule with two carbons, is then bound to oxaloacetate, synthesizing a new six-carbon compound called citrate. This reaction allows the carbon atoms in the compounds to be moved further down the citric acid cycle in an easily transportable molecule, where they will take part in a series of metabolic transformations by which the cell generates more ATP.


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