title: The return of metabolism: biochemistry and physiology of the pentose phosphate pathway.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors.forename: Anna
authors.initials: A
authors.lastname: Stincone
authors.affiliation: Max Delbrueck Centre for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
authors.affiliation: Department of Gastroenterology and Hepatology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Cramer
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Centre Amsterdam, De Boelelaaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Mirjam M C
authors.initials: MM
authors.lastname: Wamelink
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors.forename: Kate
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, U.K.
authors.forename: Eric
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors.forename: Viridiana
authors.initials: V
authors.lastname: Olin-Sandoval
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors.forename: Nana-Maria
authors.initials: NM
authors.lastname: Grüning
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestr 73, 14195 Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Krüger
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tauqeer Alam
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Keller
authors.affiliation: Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, A-5020 Salzburg, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Breitenbach
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cancer Research UK Cambridge Research Institute (CRI), Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, U.K.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
authors.affiliation: Department of Chemistry, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, 08544 NJ, U.S.A.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.|Division of Physiology and Metabolism, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7, U.K.
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
mesh_terms: D006801:Humans; D008659:Metabolic Diseases / Q000503:physiopathology; D008660:Metabolism / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000235:genetics / Q000502:physiology*
keywords: NADPH; cancer; glucose 6‐phosphate dehydrogenase; glycolysis; host–pathogen interactions; inherited metabolic disease; metabolic engineering; metabolism of infection; metabolomics; oxidative stress; parasitic protozoa; pentose phosphate pathway; stem cells