d-3-Phosphoglycerate dehydrogenase (PGDH) catalyzes the first reaction in the phosphorylated pathway of l-serine biosynthesis. In Mycobacterium tuberculosis, it is a type 1 enzyme (mtPGDH) in that it contains both an ACT domain and an ASB domain in addition to a catalytic domain. The published crystal structures (Protein Data Bank entries 1YGY and 3DC2) show a tartrate molecule interacting with cationic residues at the ASB-ACT domain interfaces and a serine molecule bound at the ACT domain interface. These sites have previously been shown to be involved in the mechanism of serine and substrate inhibition of catalytic activity. This investigation has revealed a mechanism of allosteric quaternary structure dynamics in mtPGDH that is modulated by physiologically relevant molecules, phosphate and polyphosphate. In the absence of phosphate and polyphosphate, the enzyme exists in equilibrium between an inactive dimer and an active tetramer that is insensitive to inhibition of catalytic activity by l-serine. Phosphate induces a conversion to an active tetramer and octamer that are sensitive to inhibition of catalytic activity by l-serine. Small polyphosphates (pyrophosphate and triphosphate) induce a conversion to an active dimer that is insensitive to l-serine inhibition. The difference in the tendency of each respective dimer to form a tetramer as well as slightly altered elution positions on size exclusion chromatography indicates that there is likely a conformational difference between the serine sensitive and insensitive states. This appears to constitute a unique mechanism in type 1 PGDHs that may be unique in pathogenic Mycobacterium species and may provide the organisms with a unique metabolic advantage.