Enoyl-acyl carrier protein reductase

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Enoyl-acyl carrier protein reductase (ENR) is an enzyme that plays a crucial role in the fatty acid synthesis pathway in bacteria, plants, and apicomplexan parasites. This enzyme is responsible for catalyzing the reduction of enoyl-acyl carrier protein (ACP) substrates, which is a critical step in the process of elongating fatty acids. ENR is a target for the development of antibiotics and antimalarial drugs, due to its essential role in the lipid metabolism of pathogenic microorganisms and its absence in animals, making it an attractive target for drug development.

Function

ENR catalyzes the NADH- or NADPH-dependent reduction of the double bond in enoyl-ACP, a key step in the fatty acid elongation cycle. This reaction converts the trans-2-enoyl-ACP to a fully saturated acyl-ACP. The process is vital for the biosynthesis of fatty acids, which are essential components of cell membranes and play roles in energy storage and signaling.

Types

There are two main types of ENR, classified based on their cofactor preference: the NADH-dependent (FabI) and the NADPH-dependent (FabK, FabL, and FabV) enzymes. FabI is the most widely studied and is found in a broad range of bacteria, including Escherichia coli. FabK is identified in certain bacteria such as Streptococcus pneumoniae, FabL in Bacillus subtilis, and FabV in Vibrio cholerae.

Clinical Significance

Due to its essential role in microbial fatty acid synthesis and absence in mammals, ENR is a target for antibiotic development. Inhibitors of ENR, such as triclosan and isoniazid, have been used to treat bacterial infections and tuberculosis, respectively. The development of resistance to these drugs, however, has prompted the search for new ENR inhibitors.

Structural Insights

The crystal structures of several ENR enzymes have been solved, providing insights into their mechanism of action and facilitating the design of specific inhibitors. These structures reveal a conserved architecture and a binding pocket for the NAD(P)H cofactor, which is critical for the enzyme's catalytic activity.

Drug Development

Research into ENR inhibitors is an active area of drug development, particularly for antimalarial and antibacterial agents. The challenge lies in designing molecules that are specific to the microbial ENR and do not affect the human fatty acid synthesis enzymes.

Conclusion

Enoyl-acyl carrier protein reductase is a vital enzyme in the fatty acid synthesis pathway of many microorganisms. Its unique presence in pathogens and absence in humans make it an attractive target for the development of new antimicrobial agents. Understanding the structure and function of ENR is crucial for the design of effective inhibitors that can overcome drug resistance and provide new treatments for infectious diseases.

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