Sandbox Reserved 1058

Relevance

Background

Mycobacterium tuberculosis is a respiratory infection that causes numerous fatalities throughout the world. It lives in organisms and feeds off of host cells, which indicate a variety of lipases exist within M. tuberculosis. Current drugs that are on the market now target a small number of bacterial processes like cell wall formation and chromosomal replication. Although several antibiotics exist, all of them target these same mechanisms of inhibition. These commonalities have led to the prevalence of different multi-drug resistant (MDR) tuberculosis strains. Due to the high level of resistance, finding a lasting treatment for MDR TB infections has become very problematic. Studies into new mechanisms of inhibition will be crucial to prevent widespread outbreaks.

Clinical Implications

Isocitrate lyase plays a key role in survival of M. tuberculosis by sustaining intracellular infections in inflammatory respiratory macrophages. Used in the citric acid cycle, isocitrate lyase is the first enzyme catalyzing the carbon conserving glyoxylate pathway. This glyoxylate pathway has not been observed in mammals and thus presents a unique drug target to solely attack TB infections.

Protein Structure

Crystal Structure

Figure 1. Structure of Isocitrate Lyase. Quaternary structure is comprised of four subunits forming an alpha/beta barrel.

Isocitrate lyase is a tetramer with 222 symmetry. Each subunit is composed of 14 alpha helices and 14 beta sheets. A unique structural feature of this enzyme is a phenomenon called "helix swapping" GREEN BUTTON. Helix swapping is observed between two monomers to form stable dimers. The 11th and 12th helices of each monomer exchange three dimensional placement with the respective helices of the opposite monomer GREEN BUTTON. Due to the 222 symmetry observed, only two dimers form than combine to form the observed tetramer.

Function

Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.