Orotate reductase (NADPH)

Orotate reductase (NADPH) is an enzyme that catalyzes the reduction of orotate to dihydroorotate, a crucial step in the de novo biosynthesis of pyrimidines. This enzyme utilizes NADPH (nicotinamide adenine dinucleotide phosphate) as a reducing agent, providing the necessary electrons for the reaction. The systematic name of the enzyme is (S)-dihydroorotate:NADP+ oxidoreductase.

The enzyme's reaction can be summarized as follows:

orotate + NADPH + H⁺ ⇌ (S)-dihydroorotate + NADP⁺

Orotate reductase (NADPH) is found in various organisms, from bacteria to mammals, reflecting the fundamental importance of pyrimidine synthesis for cell growth and function. In eukaryotes, the enzyme is often associated with other enzymes in the pyrimidine biosynthetic pathway, forming a multi-enzyme complex.

Inhibition of orotate reductase (NADPH) can disrupt pyrimidine biosynthesis, leading to various cellular effects, including decreased DNA and RNA synthesis. Therefore, it has been a target for drug development, particularly in the context of treating cancer and other diseases involving rapid cell proliferation. The enzyme's activity and regulation are intricately linked to the overall metabolic state of the cell. Mutations in genes encoding orotate reductase can lead to hereditary orotic aciduria, a metabolic disorder characterized by the excessive excretion of orotic acid in the urine.