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Elementary Flux Mode Analysis Revealed Cyclization Pathway as a Powerful Way for NADPH Regeneration of Central Carbon Metabolism.

Rui B, Yi Y, Shen T, Zheng M, Zhou W, Du H, Fan Y, Wang Y, Zhang Z, Xu S, Liu Z, Wen H, Xie X - PLoS ONE (2015)

Bottom Line: The clustering results were used to study the relationship between the flux of total NADPH regeneration and the flux in each NADPH producing enzyme.The results identified several reaction combinations supporting high NADPH regeneration, which are proven to be feasible in cells via thermodynamic analysis and coincident with a great deal of previous experimental report.These findings suggested cyclization pathways as a powerful way for NADPH regeneration capacity of bacterial central carbon metabolism.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science, Anhui Agricultural University, Hefei, China.

ABSTRACT
NADPH regeneration capacity is attracting growing research attention due to its important role in resisting oxidative stress. Besides, NADPH availability has been regarded as a limiting factor in production of industrially valuable compounds. The central carbon metabolism carries the carbon skeleton flux supporting the operation of NADPH-regenerating enzyme and offers flexibility in coping with NADPH demand for varied intracellular environment. To acquire an insightful understanding of its NADPH regeneration capacity, the elementary mode method was employed to compute all elementary flux modes (EFMs) of a network representative of central carbon metabolism. Based on the metabolic flux distributions of these modes, a cluster analysis of EFMs with high NADPH regeneration rate was conducted using the self-organizing map clustering algorithm. The clustering results were used to study the relationship between the flux of total NADPH regeneration and the flux in each NADPH producing enzyme. The results identified several reaction combinations supporting high NADPH regeneration, which are proven to be feasible in cells via thermodynamic analysis and coincident with a great deal of previous experimental report. Meanwhile, the reaction combinations showed some common characteristics: there were one or two decarboxylation oxidation reactions in the combinations that produced NADPH and the combination constitution included certain gluconeogenesis pathways. These findings suggested cyclization pathways as a powerful way for NADPH regeneration capacity of bacterial central carbon metabolism.

No MeSH data available.


Six cyclization pathways supporting high NADPH generation.Red hollow blocks represent the enzymes, the black circles are the metabolites, and the blue number is the flux value of cluster center of each category. The width of the brown edges is proportional to the passed flux. The abbreviations of enzymes and metabolites are as shown in S1 Appendix and S2 Appendix. The reactions in black color provide the initial carbon skeleton for a cyclization pathway. The reactions in red color are part carrying out oxidative decarboxylation and NADPH generation. The purple pathway is the gluconeogenesis pathway, and the yellow arrow represents the reaction not in the target cycle. In Fig 4a, the cluster is the ath cluster in Fig 3, containing the PP-EMP cycle. In Fig 4b, the cluster is the eth cluster in Fig 3, containing PP-ED-EMP cycle 1, PP-ED-EMP cycle 2 and ME-TCA cycle. In Fig 4c, the cluster is the jth cluster in Fig 3, containing ME-PPC cycle. In Fig. 4d, the cluster is the jth cluster in Fig 3, containing ME-GLX cycle.
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pone.0129837.g004: Six cyclization pathways supporting high NADPH generation.Red hollow blocks represent the enzymes, the black circles are the metabolites, and the blue number is the flux value of cluster center of each category. The width of the brown edges is proportional to the passed flux. The abbreviations of enzymes and metabolites are as shown in S1 Appendix and S2 Appendix. The reactions in black color provide the initial carbon skeleton for a cyclization pathway. The reactions in red color are part carrying out oxidative decarboxylation and NADPH generation. The purple pathway is the gluconeogenesis pathway, and the yellow arrow represents the reaction not in the target cycle. In Fig 4a, the cluster is the ath cluster in Fig 3, containing the PP-EMP cycle. In Fig 4b, the cluster is the eth cluster in Fig 3, containing PP-ED-EMP cycle 1, PP-ED-EMP cycle 2 and ME-TCA cycle. In Fig 4c, the cluster is the jth cluster in Fig 3, containing ME-PPC cycle. In Fig. 4d, the cluster is the jth cluster in Fig 3, containing ME-GLX cycle.

Mentions: Several different cyclized flux modes with high NADPH availability were observed in the clustering results, namely the PP-EMP cycle, PP-ED-EMP cycle 1, PP-ED-EMP cycle 2, and ME-PPC cycle, ME-GLX cycle and ME-TCA cycle (Table 1 and Fig 4). The chemical reactions of each of the six modes were added according to the individual occurrence coefficient of each reaction, to derive the net reaction equation for each reaction (Table 1). The chemical reaction equation shows that the PP-EMP cycle, ME-TCA cycle and ME-GLX cycle break the C-C bond and releases energy, thereby generating NADPH, while the other three modes generate NADPH by transferring reductive equivalent from NADH.


Elementary Flux Mode Analysis Revealed Cyclization Pathway as a Powerful Way for NADPH Regeneration of Central Carbon Metabolism.

Rui B, Yi Y, Shen T, Zheng M, Zhou W, Du H, Fan Y, Wang Y, Zhang Z, Xu S, Liu Z, Wen H, Xie X - PLoS ONE (2015)

Six cyclization pathways supporting high NADPH generation.Red hollow blocks represent the enzymes, the black circles are the metabolites, and the blue number is the flux value of cluster center of each category. The width of the brown edges is proportional to the passed flux. The abbreviations of enzymes and metabolites are as shown in S1 Appendix and S2 Appendix. The reactions in black color provide the initial carbon skeleton for a cyclization pathway. The reactions in red color are part carrying out oxidative decarboxylation and NADPH generation. The purple pathway is the gluconeogenesis pathway, and the yellow arrow represents the reaction not in the target cycle. In Fig 4a, the cluster is the ath cluster in Fig 3, containing the PP-EMP cycle. In Fig 4b, the cluster is the eth cluster in Fig 3, containing PP-ED-EMP cycle 1, PP-ED-EMP cycle 2 and ME-TCA cycle. In Fig 4c, the cluster is the jth cluster in Fig 3, containing ME-PPC cycle. In Fig. 4d, the cluster is the jth cluster in Fig 3, containing ME-GLX cycle.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472234&req=5

pone.0129837.g004: Six cyclization pathways supporting high NADPH generation.Red hollow blocks represent the enzymes, the black circles are the metabolites, and the blue number is the flux value of cluster center of each category. The width of the brown edges is proportional to the passed flux. The abbreviations of enzymes and metabolites are as shown in S1 Appendix and S2 Appendix. The reactions in black color provide the initial carbon skeleton for a cyclization pathway. The reactions in red color are part carrying out oxidative decarboxylation and NADPH generation. The purple pathway is the gluconeogenesis pathway, and the yellow arrow represents the reaction not in the target cycle. In Fig 4a, the cluster is the ath cluster in Fig 3, containing the PP-EMP cycle. In Fig 4b, the cluster is the eth cluster in Fig 3, containing PP-ED-EMP cycle 1, PP-ED-EMP cycle 2 and ME-TCA cycle. In Fig 4c, the cluster is the jth cluster in Fig 3, containing ME-PPC cycle. In Fig. 4d, the cluster is the jth cluster in Fig 3, containing ME-GLX cycle.
Mentions: Several different cyclized flux modes with high NADPH availability were observed in the clustering results, namely the PP-EMP cycle, PP-ED-EMP cycle 1, PP-ED-EMP cycle 2, and ME-PPC cycle, ME-GLX cycle and ME-TCA cycle (Table 1 and Fig 4). The chemical reactions of each of the six modes were added according to the individual occurrence coefficient of each reaction, to derive the net reaction equation for each reaction (Table 1). The chemical reaction equation shows that the PP-EMP cycle, ME-TCA cycle and ME-GLX cycle break the C-C bond and releases energy, thereby generating NADPH, while the other three modes generate NADPH by transferring reductive equivalent from NADH.

Bottom Line: The clustering results were used to study the relationship between the flux of total NADPH regeneration and the flux in each NADPH producing enzyme.The results identified several reaction combinations supporting high NADPH regeneration, which are proven to be feasible in cells via thermodynamic analysis and coincident with a great deal of previous experimental report.These findings suggested cyclization pathways as a powerful way for NADPH regeneration capacity of bacterial central carbon metabolism.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science, Anhui Agricultural University, Hefei, China.

ABSTRACT
NADPH regeneration capacity is attracting growing research attention due to its important role in resisting oxidative stress. Besides, NADPH availability has been regarded as a limiting factor in production of industrially valuable compounds. The central carbon metabolism carries the carbon skeleton flux supporting the operation of NADPH-regenerating enzyme and offers flexibility in coping with NADPH demand for varied intracellular environment. To acquire an insightful understanding of its NADPH regeneration capacity, the elementary mode method was employed to compute all elementary flux modes (EFMs) of a network representative of central carbon metabolism. Based on the metabolic flux distributions of these modes, a cluster analysis of EFMs with high NADPH regeneration rate was conducted using the self-organizing map clustering algorithm. The clustering results were used to study the relationship between the flux of total NADPH regeneration and the flux in each NADPH producing enzyme. The results identified several reaction combinations supporting high NADPH regeneration, which are proven to be feasible in cells via thermodynamic analysis and coincident with a great deal of previous experimental report. Meanwhile, the reaction combinations showed some common characteristics: there were one or two decarboxylation oxidation reactions in the combinations that produced NADPH and the combination constitution included certain gluconeogenesis pathways. These findings suggested cyclization pathways as a powerful way for NADPH regeneration capacity of bacterial central carbon metabolism.

No MeSH data available.