The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner-Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch. The oxidative branch is highly active in most eukaryotes and converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate and NADPH. The latter function is critical to maintain redox balance under stress situations, when cells proliferate rapidly, in ageing, and for the 'Warburg effect' of cancer cells. The non-oxidative branch instead is virtually ubiquitous, and metabolizes the glycolytic intermediates fructose 6-phosphate and glyceraldehyde 3-phosphate as well as sedoheptulose sugars, yielding ribose 5-phosphate for the synthesis of nucleic acids and sugar phosphate precursors for the synthesis of amino acids. Whereas the oxidative PPP is considered unidirectional, the non-oxidative branch can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand. These functions require dynamic regulation of the PPP pathway that is achieved through hierarchical interactions between transcriptome, proteome and metabolome. Consequently, the biochemistry and regulation of this pathway, while still unresolved in many cases, are archetypal for the dynamics of the metabolic network of the cell. In this comprehensive article we review seminal work that led to the discovery and description of the pathway that date back now for 80 years, and address recent results about genetic and metabolic mechanisms that regulate its activity. These biochemical principles are discussed in the context of PPP deficiencies causing metabolic disease and the role of this pathway in biotechnology, bacterial and parasite infections, neurons, stem cell potency and cancer metabolism.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/brv.12140

The return of metabolism: biochemistry and physiology of the pentose phosphate pathway

Carbohydrates mediate their conversion to triglycerides in the liver by promoting both rapid posttranslational activation of rate-limiting glycolytic and lipogenic enzymes and transcriptional induction of the genes encoding many of these same enzymes. The mechanism by which elevated carbohydrate levels affect transcription of these genes remains unknown. Here we report the purification and identification of a transcription factor that recognizes the carbohydrate response element (ChRE) within the promoter of the L-type pyruvate kinase (LPK) gene. The DNA-binding activity of this ChRE-binding protein (ChREBP) in rat livers is specifically induced by a high carbohydrate diet. ChREBP's DNA-binding specificity in vitro precisely correlates with promoter activity in vivo. Furthermore, forced ChREBP overexpression in primary hepatocytes activates transcription from the L-type Pyruvate kinase promoter in response to high glucose levels. The DNA-binding activity of ChREBP can be modulated in vitro by means of changes in its phosphorylation state, suggesting a possible mode of glucose-responsive regulation. ChREBP is likely critical for the optimal long-term storage of excess carbohydrates as fats, and may contribute to the imbalance between nutrient utilization and storage characteristic of obesity.

https://www.pnas.org/content/pnas/98/16/9116.full.pdf

A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver

The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing.

Ions and energy in mammalian brain.

https://www.cell.com/cell/pdf/S0092-8674(13)01162-8.pdf

PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells

Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies.

Multimolecular forms of pyruvate kinase. II. Purification of M 2 -type pyruvate kinase from Yoshida ascites hepatoma 130 cells and comparative studies on the enzymological and immunological properties of the three types of pyruvate kinases, L, M 1 , and M 2 .

Studies on pyruvate kinase (PK) deficiency. II. Electrophoretic, kinetic and immunological studies on pyruvate kinase of erythrocytes and other tissues.

Kiichi Imamura

Papers

Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies.

Multimolecular forms of pyruvate kinase. II. Purification of M 2 -type pyruvate kinase from Yoshida ascites hepatoma 130 cells and comparative studies on the enzymological and immunological properties of the three types of pyruvate kinases, L, M 1 , and M 2 .

Studies on pyruvate kinase (PK) deficiency. II. Electrophoretic, kinetic and immunological studies on pyruvate kinase of erythrocytes and other tissues.

Electrophoretic and kinetic studies of mutant erythrocyte pyruvate kinases.

Interaction between synthetic ATP analogues and actomyosin systems. IV.