Phosphatase Subfamily PGAM

Phosphatase Classification: Fold HP: Superfamily HP: HP, branch1 family: Subfamily PGAM

PGAMs mainly function as glycolytic enzymes regulating intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Human BPGM is a 2,3-bisphosphoglycerate mutase.

Evolution

PGAM is found in most eukaryotic genomes with duplication in individual lineages. For instance, human has four PGAMs and yeast has three. They emerged by independent duplication events.

Domain

PGAM has single domain, a HP1-family phosphatase domain.

Catalytic activity

Human has four members:

• BPGM: 2,3-bisphosphoglycerate mutase. Bisphosphoglycerate mutase is an erythrocyte-specific en- zyme catalyzing a series of intermolecular phosphoryl group transfer reactions. Its main function is to synthesize 2,3- bisphosphoglycerate [1, 2].
• PGAM1: phosphoglycerate mutase 1 (brain). Glycolytic enzyme PGAM1 regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. This is the mechanism behind oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells [3, 4]. NAD+-dependent deacetylase Sirt1 deacetylates phosphoglycerate mutase-1 (PGAM1) and attenuates catalytic activity [5].
• PGAM2: phosphoglycerate mutase 2 (muscle). Glycolytic enzyme PGAM expressed in muscle [6].
• PGAM4 (aka PGAM3): phosphoglycerate mutase family member 4.

References

1. Wang Y, Wei Z, Bian Q, Cheng Z, Wan M, Liu L, and Gong W. Crystal structure of human bisphosphoglycerate mutase. J Biol Chem. 2004 Sep 10;279(37):39132-8. DOI:10.1074/jbc.M405982200 |
2. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, Wang Y, Gu TL, Alečković M, LeRoy G, Kang Y, Kang HB, Seo JH, Shan C, Jin P, Gong W, Lonial S, Arellano ML, Khoury HJ, Chen GZ, Shin DM, Khuri FR, Boggon TJ, Kang S, He C, and Chen J. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun. 2013;4:1790. DOI:10.1038/ncomms2759 |
3. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, Shan C, Dai Q, Zhang L, Xie J, Gu TL, Jin P, Alečković M, LeRoy G, Kang Y, Sudderth JA, DeBerardinis RJ, Luan CH, Chen GZ, Muller S, Shin DM, Owonikoko TK, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Ye K, Boggon TJ, Kang S, He C, and Chen J. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012 Nov 13;22(5):585-600. DOI:10.1016/j.ccr.2012.09.020 |
4. Hitosugi T, Zhou L, Fan J, Elf S, Zhang L, Xie J, Wang Y, Gu TL, Alečković M, LeRoy G, Kang Y, Kang HB, Seo JH, Shan C, Jin P, Gong W, Lonial S, Arellano ML, Khoury HJ, Chen GZ, Shin DM, Khuri FR, Boggon TJ, Kang S, He C, and Chen J. Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. Nat Commun. 2013;4:1790. DOI:10.1038/ncomms2759 |
5. Hallows WC, Yu W, and Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem. 2012 Feb 3;287(6):3850-8. DOI:10.1074/jbc.M111.317404 |
6. Tsujino S, Shanske S, Sakoda S, Fenichel G, and DiMauro S. The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency. Am J Hum Genet. 1993 Mar;52(3):472-7.