Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate

Abstract

Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). Catalytic activity of PGAM1 requires its histidine phosphorylation. We show that the primary PGAM1 histidine phosphate donor is 2,3-bisphosphoglycerate (2,3-BPG), which is made from the glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) by bisphosphoglycerate mutase (BPGM). When BPGM is knocked out, 1,3-BPG can directly phosphorylate PGAM1. In this case, PGAM1 phosphorylation and activity are decreased, but nevertheless sufficient to maintain normal glycolytic flux and cellular growth rate. 3-PG, however, accumulates, leading to increased serine synthesis. Thus, one biological function of BPGM is to control glycolytic intermediate levels and thereby serine biosynthetic flux.

Antisickling Effects of Quercetin may be Associated with Modulation of Deoxyhaemoglobin, 2, 3-bisphosphoglycerate mutase, Redox Homeostasis and Alteration of Functional Chemistry in Human Sickle Erythrocytes.

“…At lower oxygen pressures, increased hemoglobin binding to red cell membranes increases reactive oxygen species generation, leading to oxidative stress, prominently observed in the microvasculature (Mohanty et al, 2014). To neutralize this challenge, the molecule 2,3-bisphosphoglycerate, abundantly present in red cells, synthesized from 1,3-bisphosphoglycerate by bisphosphoglycerate mutase, binds to deoxy-hemoglobin, thereby stabilizing it and reducing oxygen affinity (Oslund et al, 2017;Poillon et al, 1995). This may invariably have negative effects in SCD patients, thereby aggravating the already existing precarious condition.…”

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

“…ALDOA [45][46][47] and ENO1 were both found to be involved in tumorigenesis in different cancer types [48][49][50][51][52]. BPGM was reported to control serine flux via 3-phosphoglycerate [53], which may benefit cancer cell survival. However, its role in cancer is not clear.…”

Phosphoglycerate mutase 1 in cancer: A promising target for diagnosis and therapy

“…A highly reactive glycolytic intermediate 1, 3‐bisphosphoglycerate acts as potential donor and is involved in the production of ATP through phosphoglycerate kinase to directly phosphorylate PGAM1. In this case, PGAM1 function is not completely eliminated but adequated to continue the normal glycolytic pathway …”

“…In PGAM1 knockdown cells, 2, 3‐BPG expression remains stable in the occurrence of active BPGM. As a consequence of attenuated PGAM1 expression, no significant alterations are detected in mono‐PG, the oxidative pentose phosphate pathway and the serine flux (Figure ) …”

“…In this case, PGAM1 function is not completely eliminated but adequated to continue the normal glycolytic pathway. 7,25,26 4 | PGAM1 IS A LINK BETWEEN METABOLIC PATHWAYS PGAM1 provides a correlation between glycolysis and biosynthesis through its catalytic activity. 27 1, 3-bisphosphoglycerate serves as an active backup to 2, 3-bisphosphoglycerate for rapid phosphorylation of PGAM1 on its active site histidine.…”