3PGDH Inhibitors

Chemical inhibitors of 3PGDH can be characterized by their ability to interfere with the enzyme's activity either by directly binding to the active site or by modifying the enzyme's structure or stability. However, in the absence of known direct inhibitors, the focus shifts to compounds that can indirectly affect the enzyme's function through alterations in metabolic pathways and cofactor availability. 3PGDH is NAD+-dependent, and its activity is inherently linked to the cellular redox state and the concentration of its substrate, 3-phosphoglycerate. Indirect inhibitors may not bind to 3PGDH itself but can impact its activity by modulating the levels of NAD+/NADH, altering the production or availability of 3-phosphoglycerate through changes in glycolytic flux, or influencing the cellular energy status, which can have downstream effects on various biosynthetic pathways, including the serine synthesis pathway. The enzymatic activity of 3PGDH is crucial for the synthesis of L-serine, which has multiple physiological roles, ranging from serving as a precursor to other amino acids and phospholipids to playing a role in neurotransmitter synthesis and cellular proliferation. The regulation of 3PGDH is complex and involves feedback inhibition by L-serine itself, as well as transcriptional and post-translational modifications. Therefore, chemicals that impact these regulatory mechanisms can also serve as indirect inhibitors of 3PGDH. Given that the enzyme is part of a larger network of metabolic reactions, compounds that target upstream or downstream enzymes in the serine synthesis or glycolytic pathways could also have a secondary inhibitory effect on 3PGDH. The exploration of indirect inhibitors offers an alternative approach to modulating the enzyme's activity, revealing novel insights into the regulation of serine biosynthesis and its associated metabolic networks.