The amino acid proline has multifaceted roles in various organisms including carbon and nitrogen flux, protein synthesis, osmolyte balance, and stress protection. Proline homeostasis is important in human disease, where inborn errors in proline metabolism are thought to lead to neurological dysfunctions such as schizophrenia and febrile seizures, as well as errors in systemic ammonia detoxification and developmental disorders such as skin hyperelasticity (1-3). Recently it was shown that mutations that disrupt proline biosynthesis are linked with progeroid features and osteopenia that are part of the autosomal recessive cutis laxa syndrome(4).In bacteria and plants, proline metabolism is responsive to various environmental stresses such as drought, osmotic pressure, or ultraviolent irradiation leading to proline accumulation as a survival mechanism (5-6). Overall proline has become a very important metabolite that is thought to be involved in many cellular processes.
The overall goal of our research is to understand the mechanisms of proline metabolic enzymes and how proline metabolism impacts stress response and the intracellular redox environment. All organisms convert proline to glutamate in two enzymatic steps. In the first step, proline is oxidized to ∆1-pyrroline-5-carboxylate (P5C) by the flavin-dependent enzyme proline dehydrogenase (PRODH). P5C is then hydrolyzed nonenzymatically to glutamic semialdehyde (GSA), which is oxidized to glutamate by the NAD dependent enzyme, P5C dehydrogenase (P5CDH). In Gram-negative bacteria, the PRODH and P5CDH domains are fused onto the same polypeptide called the proline utilization A (PutA) protein. Proline biosynthesis from glutamate involves three enzymatic steps.The initial two steps are catalyzed by g-glutamyl kinase (GK) and g-glutamyl phosphate reductase (GPR). GK generates g-glutamyl phosphate, which is then reduced by GPR to produce GSA.In bacteria and lower eukaryotes such as yeast, GK and GPR are discrete monofunctional enzymes.In animals and plants, the GK and GPR domains are fused together into the bifunctional enzyme P5C synthase (P5CS). After GSA cyclizes to P5C, P5C is reduced to proline by P5C reductase (P5CR).
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