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

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          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.

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          Most cited references 365

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          On the origin of cancer cells.

           O WARBURG (1956)
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            TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

            The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.
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              Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR.

              A method for obtaining strongly polarized nuclear spins in solution has been developed. The method uses low temperature, high magnetic field, and dynamic nuclear polarization (DNP) to strongly polarize nuclear spins in the solid state. The solid sample is subsequently dissolved rapidly in a suitable solvent to create a solution of molecules with hyperpolarized nuclear spins. The polarization is performed in a DNP polarizer, consisting of a super-conducting magnet (3.35 T) and a liquid-helium cooled sample space. The sample is irradiated with microwaves at approximately 94 GHz. Subsequent to polarization, the sample is dissolved by an injection system inside the DNP magnet. The dissolution process effectively preserves the nuclear polarization. The resulting hyperpolarized liquid sample can be transferred to a high-resolution NMR spectrometer, where an enhanced NMR signal can be acquired, or it may be used as an agent for in vivo imaging or spectroscopy. In this article we describe the use of the method on aqueous solutions of [13C]urea. Polarizations of 37% for 13C and 7.8% for 15N, respectively, were obtained after the dissolution. These polarizations correspond to an enhancement of 44,400 for 13C and 23,500 for 15N, respectively, compared with thermal equilibrium at 9.4 T and room temperature. The method can be used generally for signal enhancement and reduction of measurement time in liquid-state NMR and opens up for a variety of in vitro and in vivo applications of DNP-enhanced NMR.
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                Author and article information

                Journal
                0414576
                1122
                Biol Rev Camb Philos Soc
                Biol Rev Camb Philos Soc
                Biological reviews of the Cambridge Philosophical Society
                1464-7931
                1469-185X
                31 May 2015
                22 September 2014
                August 2015
                22 March 2016
                : 90
                : 3
                : 927-963
                Affiliations
                [1 ]Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K
                [2 ]Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K
                [3 ]Max Delbrueck Centre for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
                [4 ]Department of Gastroenterology and Hepatology, Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
                [5 ]Metabolic Unit, Department of Clinical Chemistry, VU University Medical Centre Amsterdam, De Boelelaaan 1117, 1081 HV, Amsterdam, The Netherlands
                [6 ]Cancer Research UK, Beatson Institute, Switchback Road, Glasgow G61 1BD, U.K
                [7 ]Max Planck Institute for Molecular Genetics, Ihnestr 73, 14195 Berlin, Germany
                [8 ]Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, A-5020, Salzburg, Austria
                [9 ]Cancer Research UK Cambridge Research Institute (CRI), Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, U.K
                [10 ]Department of Chemistry, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, 08544 NJ, U.S.A
                [11 ]Division of Physiology and Metabolism, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7, U.K
                Author notes
                [* ]Address for correspondence (Tel: +44 1223 761346; mr559@ 123456cam.ac.uk )
                Article
                NIHMS695070
                10.1111/brv.12140
                4470864
                25243985

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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