Dihydropteroate synthase

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Dihydropteroate synthase (DHPS) is an enzyme that plays a crucial role in the folate biosynthesis pathway. It catalyzes the formation of dihydropteroate from para-aminobenzoic acid (PABA) and dihydropterin pyrophosphate (DHPP). This reaction is essential for the production of tetrahydrofolate, a cofactor involved in the synthesis of nucleotides and amino acids.

Function

DHPS is responsible for the condensation of PABA with DHPP to form dihydropteroate, which is subsequently converted into dihydrofolate and then into tetrahydrofolate. Tetrahydrofolate is vital for the transfer of one-carbon units in various metabolic processes, including the synthesis of purines, thymidylate, and certain amino acids.

Mechanism

The enzyme operates through a mechanism that involves the nucleophilic attack of the amino group of PABA on the pyrophosphate group of DHPP. This reaction results in the formation of dihydropteroate and the release of pyrophosphate.

Inhibition and Antibiotic Resistance

DHPS is a target for sulfonamide antibiotics, which are structural analogs of PABA. These antibiotics competitively inhibit the enzyme, thereby blocking folate synthesis and bacterial growth. However, resistance to sulfonamides can occur through mutations in the DHPS gene, which reduce the binding affinity of the antibiotic to the enzyme.

Clinical Significance

Mutations in the DHPS gene can lead to resistance against sulfonamide antibiotics, posing a challenge in the treatment of bacterial infections. Understanding the structure and function of DHPS is crucial for the development of new antibiotics and the management of antibiotic resistance.

Structure

The structure of DHPS typically consists of a core domain that binds to DHPP and a flexible loop that interacts with PABA. The enzyme is usually found as a homodimer, with each subunit contributing to the active site.

Research and Development

Ongoing research aims to elucidate the detailed structure of DHPS and its interaction with inhibitors. This knowledge is essential for designing new drugs that can overcome resistance mechanisms.

See also

• Folate
• Sulfonamide
• Antibiotic resistance
• Enzyme
• Metabolic pathway