Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and suppor...Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.展开更多
The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building bl...The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth.However,genetic evidence linking the two pathways is largely unclear.In this study,we identified 6-phosphogluconate dehydrogenase 2(PGD2),the rate-limiting enzyme of the cytosolic OPP pathway,through suppressor screening of arogenate dehydrogenase 2(adh2)in Arabidopsis.Our data indicated that a single amino acid substitution at position 63(glutamic acid to lysine)of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2,thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2.Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue.Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities,thus exhibiting distinct AAAs producing capability.These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2.The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.展开更多
The recent discovery of the Entner-Doudoroff(ED)pathway as a third glycolytic route beside Embden-Meyerhof-Parnas(EMP)and oxidative pentose phosphate(OPP)pathway in oxygenic photoautotrophs requires a revision of thei...The recent discovery of the Entner-Doudoroff(ED)pathway as a third glycolytic route beside Embden-Meyerhof-Parnas(EMP)and oxidative pentose phosphate(OPP)pathway in oxygenic photoautotrophs requires a revision of their central carbohydrate metabolism.In this study,unexpectedly,we observed that deletion of the ED pathway alone,and even more pronounced in combination with other glycolytic routes,diminished photoautotrophic growth in continuous light in the cyanobacterium Synechocystis sp.PCC 6803.Furthermore,we found that the ED pathway is required for optimal glycogen catabolism in parallel to an operating Calvin-Benson-Bassham(CBB)cycle.It is counter-intuitive that glycolytic routes,which are a reverse to the CBB cycle and do not provide any additional biosynthetic intermediates,are important under photoautotrophic conditions.However,observations on the ability to reactivate an arrested CBB cycle revealed that they form glycolytic shunts that tap the cellular carbohydrate reservoir to replenish the cycle.Taken together,our results suggest that the classical view of the CBB cycle as an autocatalytic,completely autonomous cycle that exclusively relies on its own enzymes and C02 fixation to regenerate ribulose-1,5-bisphosphate for Rubisco is an oversimplification.We propose that in common with other known autocatalytic cycles,the CBB cycle likewise relies on anaplerotic reactions to compensate for the depletion of intermediates,particularly in transition states and under fluctuating light conditions that are common in nature.展开更多
基金We apologize to those authors whose excellent work could not be cited due to space constraints. This work was supported by the Start-Up Package Fund from Tsinghua University to J.P. and the grant （Grants No. 2010CB912804 and 31030046 to WM） from National Natural Science Foundation of China.
文摘Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
基金supported by the National Key Research and Development Program of China(2019YFA0903900)the National Natural Science Foundation of China(32300233)+1 种基金Guangdong Provincial Key Laboratory of Synthetic Genomics(2023B1212060054)Shenzhen Key Laboratory of Synthetic Genomics(ZDSYS201802061806209).
文摘The oxidative pentose phosphate(OPP)pathway provides metabolic intermediates for the shikimate pathway and directs carbon flow to the biosynthesis of aromatic amino acids(AAAs),which serve as basic protein building blocks and precursors of numerous metabolites essential for plant growth.However,genetic evidence linking the two pathways is largely unclear.In this study,we identified 6-phosphogluconate dehydrogenase 2(PGD2),the rate-limiting enzyme of the cytosolic OPP pathway,through suppressor screening of arogenate dehydrogenase 2(adh2)in Arabidopsis.Our data indicated that a single amino acid substitution at position 63(glutamic acid to lysine)of PGD2 enhanced its enzyme activity by facilitating the dissociation of products from the active site of PGD2,thus increasing the accumulation of AAAs and partially restoring the defective phenotype of adh2.Phylogenetic analysis indicated that the point mutation occurred in a well-conserved amino acid residue.Plants with different amino acids at this conserved site of PGDs confer diverse catalytic activities,thus exhibiting distinct AAAs producing capability.These findings uncover the genetic link between the OPP pathway and AAAs biosynthesis through PGD2.The gain-of-function point mutation of PGD2 identified here could be considered as a potential engineering target to alter the metabolic flux for the production of AAAs and downstream compounds.
基金financed by grants from the Deutsche Forschungsgemeinschaft(GU1522/1-1,GU1522/2-1,WI1796/3-1,and FOR 2816)the Bundesministerium fur Bildung und Forschung(FP309).
文摘The recent discovery of the Entner-Doudoroff(ED)pathway as a third glycolytic route beside Embden-Meyerhof-Parnas(EMP)and oxidative pentose phosphate(OPP)pathway in oxygenic photoautotrophs requires a revision of their central carbohydrate metabolism.In this study,unexpectedly,we observed that deletion of the ED pathway alone,and even more pronounced in combination with other glycolytic routes,diminished photoautotrophic growth in continuous light in the cyanobacterium Synechocystis sp.PCC 6803.Furthermore,we found that the ED pathway is required for optimal glycogen catabolism in parallel to an operating Calvin-Benson-Bassham(CBB)cycle.It is counter-intuitive that glycolytic routes,which are a reverse to the CBB cycle and do not provide any additional biosynthetic intermediates,are important under photoautotrophic conditions.However,observations on the ability to reactivate an arrested CBB cycle revealed that they form glycolytic shunts that tap the cellular carbohydrate reservoir to replenish the cycle.Taken together,our results suggest that the classical view of the CBB cycle as an autocatalytic,completely autonomous cycle that exclusively relies on its own enzymes and C02 fixation to regenerate ribulose-1,5-bisphosphate for Rubisco is an oversimplification.We propose that in common with other known autocatalytic cycles,the CBB cycle likewise relies on anaplerotic reactions to compensate for the depletion of intermediates,particularly in transition states and under fluctuating light conditions that are common in nature.
