Isocitrate lyase

ICL catalyzed rxn

Isocitrate lyase (ICL) is an enzyme that plays a crucial role in the metabolism of cells, particularly in the glyoxylate cycle, which is an alternative to the Krebs cycle (also known as the citric acid cycle or TCA cycle) in plants, bacteria, protists, and fungi. This enzyme catalyzes the cleavage of isocitrate into succinate and glyoxylate, a critical step that enables organisms to convert fatty acids into carbohydrates.

Function

Isocitrate lyase is pivotal in the glyoxylate cycle, allowing organisms that possess this pathway to survive on compounds that are two carbons in length, such as acetate, ethanol, or fatty acids, by bypassing the decarboxylation steps of the Krebs cycle. This is particularly important for seed germination in plants, where fatty acids stored in seeds are converted into sugars needed for growth, and in microorganisms during growth on carbon sources such as acetate or ethanol.

Structure

The structure of isocitrate lyase has been determined through X-ray crystallography. It typically functions as a tetramer and requires magnesium or manganese ions for its activity. The active site of the enzyme binds to isocitrate, facilitating its cleavage into succinate and glyoxylate.

Mechanism

The mechanism of isocitrate lyase involves the abstraction of the hydrogen atom from C2 of isocitrate, followed by the cleavage of the C2-C3 bond. This reaction results in the formation of succinate and glyoxylate. The enzyme's active site contains residues that stabilize the transition state and facilitate the cleavage.

Biological Importance

Isocitrate lyase is essential for the survival of plants, bacteria, fungi, and protists in environments where the primary source of carbon is in the form of two-carbon compounds. In pathogenic microorganisms, such as Mycobacterium tuberculosis, the enzyme is critical for survival within the host organism, making it a target for the development of new antimicrobial agents.

Clinical Significance

Given its role in the metabolism of pathogenic microorganisms, isocitrate lyase has been studied as a potential target for antibacterial and antifungal drugs. Inhibitors of isocitrate lyase could potentially block the glyoxylate cycle, thereby limiting the ability of pathogens to utilize fatty acids and survive within the host.

Research

Research on isocitrate lyase includes studies on its structure, mechanism, and role in various metabolic pathways. Additionally, the development of inhibitors as potential therapeutic agents against diseases caused by pathogenic microorganisms that rely on the glyoxylate cycle is an active area of research.