# BPGM

## Overview
The BPGM gene encodes the enzyme bisphosphoglycerate mutase, which plays a crucial role in the glycolytic pathway, particularly in erythrocytes (red blood cells). This enzyme is responsible for the conversion of 1,3-bisphosphoglycerate (1,3-BPG) to 2,3-bisphosphoglycerate (2,3-BPG), a critical regulator of hemoglobin's oxygen-binding affinity and thus, oxygen delivery to tissues (Lemarchandel1992Compound). The protein bisphosphoglycerate mutase, encoded by BPGM, is characterized by its distinct structural features, including a complex arrangement of alpha-helices and beta-strands, forming a functional dimer crucial for its enzymatic activity (Wang2004Crystal). Abnormalities or deficiencies in this enzyme can lead to significant clinical consequences, such as erythrocytosis, highlighting its importance in maintaining oxygen homeostasis (Hoyer2004Erythrocytosis).

## Structure
The molecular structure of human bisphosphoglycerate mutase (BPGM) is characterized by a complex arrangement of alpha-helices and beta-strands, forming a distinct alpha/beta fold similar to that observed in dPGMs from other species such as Saccharomyces cerevisiae and Escherichia coli. The BPGM monomer includes two domains, comprising six beta-strands (betaA-F) and ten alpha-helices (alpha1-10). The core of the protein features a six beta-strand sheet, with strands betaA, betaB, betaC, betaD, and betaF aligned in parallel, and strand betaE in an antiparallel configuration, surrounded by six alpha-helices (Wang2004Crystal).

In terms of quaternary structure, BPGM functions as a dimer, both in crystal form and in solution. The dimerization involves interactions between the betaC strands and alpha3 helices of the two monomers, supported by hydrophobic interactions and additional stabilizing forces such as a salt bridge between Lys-29 and Glu-72, and several hydrogen bonds involving key residues (Wang2004Crystal).

The C-terminal tail of BPGM is particularly noteworthy, as it contains residues essential for the enzyme's catalytic activities, including Glu-249 and Asp-250. Deletion of the last seven residues in this region results in the loss of all three catalytic activities of the enzyme, underscoring their critical functional role (Wang2004Crystal).

## Function
The BPGM gene encodes the enzyme bisphosphoglycerate mutase, which is essential in the glycolytic pathway, particularly within red blood cells. This enzyme primarily catalyzes the conversion of 1,3-bisphosphoglycerate (1,3-BPG) to 2,3-bisphosphoglycerate (2,3-BPG). The production of 2,3-BPG is crucial as it regulates the oxygen-binding affinity of hemoglobin, thereby influencing oxygen release from hemoglobin to tissues. This regulation is vital for maintaining adequate oxygen delivery, especially under varying physiological conditions such as changes in altitude or oxygen availability (Hoyer2004Erythrocytosis; Lemarchandel1992Compound).

In addition to its primary role, BPGM also exhibits minor activity in catalyzing the reversible conversion of 3-phosphoglycerate to 2-phosphoglycerate, although this function is predominantly carried out by phosphoglycerate mutase (PGAM) (Lemarchandel1992Compound). The enzyme is highly expressed in erythroid cells and organs rich in red blood cells, such as the spleen and placenta, underscoring its importance in erythrocyte metabolism and overall oxygen transport in the body (Xu2020Bisphosphoglycerate).

Deficiencies or abnormalities in BPGM can lead to significant alterations in erythrocyte function and oxygen delivery, as evidenced by conditions such as erythrocytosis, where there is an increased red blood cell count in response to reduced oxygen delivery to tissues (Hoyer2004Erythrocytosis). This highlights the critical role of BPGM in maintaining oxygen homeostasis and the potential consequences of its dysfunction.

## Clinical Significance
Mutations in the BPGM gene, which encodes bisphosphoglycerate mutase, are associated with hereditary erythrocytosis, a condition characterized by an increased red blood cell mass and elevated hemoglobin and hematocrit levels. This gene plays a crucial role in the synthesis of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells, affecting oxygen release from hemoglobin. Deficiencies or mutations in BPGM lead to decreased levels of 2,3-BPG, resulting in increased oxygen affinity of hemoglobin and subsequent erythrocytosis as the body attempts to compensate for reduced oxygen availability (Oliveira2018Genotype–phenotype; Bento2013Genetic).

Specific mutations, such as a leucine-to-proline substitution at codon 87 and an arginine-to-glutamine substitution, have been identified and are associated with clinically significant erythrocytosis. These mutations affect highly conserved amino acids, underscoring their importance in the gene's function (Lazana2020Uniparental). Additionally, compound heterozygous states involving mutations like arginine-to-cysteine substitution and frameshift mutations have also been linked to this condition (Lazana2020Uniparental).

In some cases, BPGM mutations do not lead to the expected decrease in p50 values, indicating a complex relationship between genotype and phenotype, which underscores the importance of comprehensive testing to understand the impact of these mutations fully (Oliveira2018Genotype–phenotype). This complexity is further highlighted by the presence of BPGM mutations in patients with normal p50 values, suggesting variable expressivity and incomplete penetrance of the mutations (Gangat2022Erythrocytosis).

## Interactions
Bisphosphoglycerate mutase (BPGM) is involved in several key protein interactions that are crucial for its function in cellular metabolism and glycolysis. BPGM interacts with Phosphoglycerate Mutase 1 (PGAM1) through its metabolic product, 2,3-bisphosphoglycerate (2,3-BPG). This interaction is essential for the phosphorylation of PGAM1, which is a critical step in the glycolytic pathway. The phosphorylation of PGAM1 by BPGM-produced 2,3-BPG facilitates PGAM1's enzymatic activity, highlighting a direct biochemical interaction between these two proteins (Oslund2017Bisphosphoglycerate).

Additionally, in the absence of BPGM, alternative phosphorylation pathways for PGAM1 have been identified. Specifically, 1,3-Bisphosphoglycerate (1,3-BPG) can directly phosphorylate PGAM1 on a specific histidine residue, serving as a backup mechanism to maintain PGAM1 activity and ensure continued glycolytic flux when BPGM is not present (Oslund2017Bisphosphoglycerate).

These interactions underscore the pivotal role of BPGM in regulating key steps in glycolysis and cellular energy metabolism, particularly through its influence on PGAM1 activity.


## References


[1. (Xu2020Bisphosphoglycerate) Guoyue Xu, Rebekah van Bruggen, Christian O. Gualtieri, Neda Moradin, Adrien Fois, Diane Vallerand, Mariana De Sa Tavares Russo, Angelia Bassenden, Wenyun Lu, Mifong Tam, Sylvie Lesage, Hélène Girouard, Daina Zofija Avizonis, Geneviève Deblois, Josef T. Prchal, Mary Stevenson, Albert Berghuis, Tom Muir, Joshua Rabinowitz, Silvia M. Vidal, Nassima Fodil, and Philippe Gros. Bisphosphoglycerate mutase deficiency protects against cerebral malaria and severe malaria-induced anemia. Cell Reports, 32(12):108170, September 2020. URL: http://dx.doi.org/10.1016/j.celrep.2020.108170, doi:10.1016/j.celrep.2020.108170. (7 citations) 10.1016/j.celrep.2020.108170](https://doi.org/10.1016/j.celrep.2020.108170)

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