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Dynamics of the Heat Stress Response of Ceramides with Different Fatty-Acyl Chain Lengths in Baker's Yeast.

Chen PW, Fonseca LL, Hannun YA, Voit EO - PLoS Comput. Biol. (2015)

Bottom Line: The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress.The details of the sphingolipid responses to heat stress are important, because they guide some of the longer-term alterations in gene expression, with which the cells adapt to the increased temperature.The analysis indicates that all enzyme activities in the system are affected and that the shapes of the time trends in activities depend on the fatty-acyl CoA chain lengths of the different ceramide species in the system.

View Article: PubMed Central - PubMed

Affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America; The George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT
The article demonstrates that computational modeling has the capacity to convert metabolic snapshots, taken sequentially over time, into a description of cellular, dynamic strategies. The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress. Using time dependent metabolic concentration data, we use a combination of mathematical modeling, reverse engineering, and optimization to infer dynamic changes in enzyme activities within the sphingolipid pathway. The details of the sphingolipid responses to heat stress are important, because they guide some of the longer-term alterations in gene expression, with which the cells adapt to the increased temperature. The analysis indicates that all enzyme activities in the system are affected and that the shapes of the time trends in activities depend on the fatty-acyl CoA chain lengths of the different ceramide species in the system.

No MeSH data available.


Related in: MedlinePlus

Structure of the proposed model of ceramide dynamics.Left panel: Detailed pathway of ceramide biosynthesis and utilization. The pathway consists of three major subsystems: synthesis and utilization of DHC (left column), synthesis and utilization of PHC (right column), and fatty acid elongation and desaturation (center column). V1, V6, V11, V16, V21, V26, V30, V34, V38 and V42 represent fluxes catalyzed by ceramide synthase. V3, V8, V13, V18, V23, and V28, V32, V36, V40 and V44 represent fluxes catalyzed by dihydroceramidase and phytoceramidase, respectively. Reactions exiting the system to the left or right, namely V5, V10, V15, V20, V25, V29, V33, V37, V41 and V45, represent fluxes catalyzed by IPC synthase, while reactions entering the system from the left or right, V2, V7, V12, V17, V22, V27, V31, V35, V39 and V43, represent fluxes catalyzed by IPCase (Isc1). V4, V9, V14, V19, V24 represent DHC hydroxylase. The vertically shown reactions represent reactions catalyzed by other enzymes, such as remodelase (V46), fatty acid elongases (V47, V48, V50, V51, V52, and V53), and desaturase (V49). The boxes marked “IPC” summarily account for the complex sphingolipids IPC, MIPC, and M(IP)2C and their inter-conversions. This simplification seems reasonable as all three, IPC, MIPC and M(IP)2C, can serve as sources for the production of DHC and PHC. Right panel: The dynamic flux estimation is partly based on some fluxes whose magnitudes we took from our previous model [13]. The table summarizes these fluxes and indicates on the right how they constrain fluxes in our present model.
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pcbi.1004373.g002: Structure of the proposed model of ceramide dynamics.Left panel: Detailed pathway of ceramide biosynthesis and utilization. The pathway consists of three major subsystems: synthesis and utilization of DHC (left column), synthesis and utilization of PHC (right column), and fatty acid elongation and desaturation (center column). V1, V6, V11, V16, V21, V26, V30, V34, V38 and V42 represent fluxes catalyzed by ceramide synthase. V3, V8, V13, V18, V23, and V28, V32, V36, V40 and V44 represent fluxes catalyzed by dihydroceramidase and phytoceramidase, respectively. Reactions exiting the system to the left or right, namely V5, V10, V15, V20, V25, V29, V33, V37, V41 and V45, represent fluxes catalyzed by IPC synthase, while reactions entering the system from the left or right, V2, V7, V12, V17, V22, V27, V31, V35, V39 and V43, represent fluxes catalyzed by IPCase (Isc1). V4, V9, V14, V19, V24 represent DHC hydroxylase. The vertically shown reactions represent reactions catalyzed by other enzymes, such as remodelase (V46), fatty acid elongases (V47, V48, V50, V51, V52, and V53), and desaturase (V49). The boxes marked “IPC” summarily account for the complex sphingolipids IPC, MIPC, and M(IP)2C and their inter-conversions. This simplification seems reasonable as all three, IPC, MIPC and M(IP)2C, can serve as sources for the production of DHC and PHC. Right panel: The dynamic flux estimation is partly based on some fluxes whose magnitudes we took from our previous model [13]. The table summarizes these fluxes and indicates on the right how they constrain fluxes in our present model.

Mentions: As mentioned above, the dynamics of ceramide species is governed by five groups of enzymes, which are shown in Fig 1 along with SPT and KDHS, which catalyze prior reactions steps. Our overall strategy for zeroing in on this sub-pathway is similar to our previous approach, although the detailed account here requires several methodological modifications, which are detailed in the section Materials and Methods. As an illustrative example, consider dihydroceramidase. In our previous study, this enzyme catalyzed a single reaction step from DHC to DHS. Now, dihydroceramidase is involved in five reactions, from C14 and C16 DHC to DHS, C18 DHC to DHS, and so on, to the conversion of C26 and C26:1 DHC into DHS. The relationships between fluxes in the previous and in the present model are shown in the right panel of Fig 2. References regarding the enzymatic reactions can be found in the section Pertinent Details of Sphingolipid Metabolism. The refined ceramide model discussed here shares many reactions with the previous sphingolipid model, but is expanded toward details regarding the availability of specific substrates.


Dynamics of the Heat Stress Response of Ceramides with Different Fatty-Acyl Chain Lengths in Baker's Yeast.

Chen PW, Fonseca LL, Hannun YA, Voit EO - PLoS Comput. Biol. (2015)

Structure of the proposed model of ceramide dynamics.Left panel: Detailed pathway of ceramide biosynthesis and utilization. The pathway consists of three major subsystems: synthesis and utilization of DHC (left column), synthesis and utilization of PHC (right column), and fatty acid elongation and desaturation (center column). V1, V6, V11, V16, V21, V26, V30, V34, V38 and V42 represent fluxes catalyzed by ceramide synthase. V3, V8, V13, V18, V23, and V28, V32, V36, V40 and V44 represent fluxes catalyzed by dihydroceramidase and phytoceramidase, respectively. Reactions exiting the system to the left or right, namely V5, V10, V15, V20, V25, V29, V33, V37, V41 and V45, represent fluxes catalyzed by IPC synthase, while reactions entering the system from the left or right, V2, V7, V12, V17, V22, V27, V31, V35, V39 and V43, represent fluxes catalyzed by IPCase (Isc1). V4, V9, V14, V19, V24 represent DHC hydroxylase. The vertically shown reactions represent reactions catalyzed by other enzymes, such as remodelase (V46), fatty acid elongases (V47, V48, V50, V51, V52, and V53), and desaturase (V49). The boxes marked “IPC” summarily account for the complex sphingolipids IPC, MIPC, and M(IP)2C and their inter-conversions. This simplification seems reasonable as all three, IPC, MIPC and M(IP)2C, can serve as sources for the production of DHC and PHC. Right panel: The dynamic flux estimation is partly based on some fluxes whose magnitudes we took from our previous model [13]. The table summarizes these fluxes and indicates on the right how they constrain fluxes in our present model.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4524633&req=5

pcbi.1004373.g002: Structure of the proposed model of ceramide dynamics.Left panel: Detailed pathway of ceramide biosynthesis and utilization. The pathway consists of three major subsystems: synthesis and utilization of DHC (left column), synthesis and utilization of PHC (right column), and fatty acid elongation and desaturation (center column). V1, V6, V11, V16, V21, V26, V30, V34, V38 and V42 represent fluxes catalyzed by ceramide synthase. V3, V8, V13, V18, V23, and V28, V32, V36, V40 and V44 represent fluxes catalyzed by dihydroceramidase and phytoceramidase, respectively. Reactions exiting the system to the left or right, namely V5, V10, V15, V20, V25, V29, V33, V37, V41 and V45, represent fluxes catalyzed by IPC synthase, while reactions entering the system from the left or right, V2, V7, V12, V17, V22, V27, V31, V35, V39 and V43, represent fluxes catalyzed by IPCase (Isc1). V4, V9, V14, V19, V24 represent DHC hydroxylase. The vertically shown reactions represent reactions catalyzed by other enzymes, such as remodelase (V46), fatty acid elongases (V47, V48, V50, V51, V52, and V53), and desaturase (V49). The boxes marked “IPC” summarily account for the complex sphingolipids IPC, MIPC, and M(IP)2C and their inter-conversions. This simplification seems reasonable as all three, IPC, MIPC and M(IP)2C, can serve as sources for the production of DHC and PHC. Right panel: The dynamic flux estimation is partly based on some fluxes whose magnitudes we took from our previous model [13]. The table summarizes these fluxes and indicates on the right how they constrain fluxes in our present model.
Mentions: As mentioned above, the dynamics of ceramide species is governed by five groups of enzymes, which are shown in Fig 1 along with SPT and KDHS, which catalyze prior reactions steps. Our overall strategy for zeroing in on this sub-pathway is similar to our previous approach, although the detailed account here requires several methodological modifications, which are detailed in the section Materials and Methods. As an illustrative example, consider dihydroceramidase. In our previous study, this enzyme catalyzed a single reaction step from DHC to DHS. Now, dihydroceramidase is involved in five reactions, from C14 and C16 DHC to DHS, C18 DHC to DHS, and so on, to the conversion of C26 and C26:1 DHC into DHS. The relationships between fluxes in the previous and in the present model are shown in the right panel of Fig 2. References regarding the enzymatic reactions can be found in the section Pertinent Details of Sphingolipid Metabolism. The refined ceramide model discussed here shares many reactions with the previous sphingolipid model, but is expanded toward details regarding the availability of specific substrates.

Bottom Line: The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress.The details of the sphingolipid responses to heat stress are important, because they guide some of the longer-term alterations in gene expression, with which the cells adapt to the increased temperature.The analysis indicates that all enzyme activities in the system are affected and that the shapes of the time trends in activities depend on the fatty-acyl CoA chain lengths of the different ceramide species in the system.

View Article: PubMed Central - PubMed

Affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America; The George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT
The article demonstrates that computational modeling has the capacity to convert metabolic snapshots, taken sequentially over time, into a description of cellular, dynamic strategies. The specific application is a detailed analysis of a set of actions with which Saccharomyces cerevisiae responds to heat stress. Using time dependent metabolic concentration data, we use a combination of mathematical modeling, reverse engineering, and optimization to infer dynamic changes in enzyme activities within the sphingolipid pathway. The details of the sphingolipid responses to heat stress are important, because they guide some of the longer-term alterations in gene expression, with which the cells adapt to the increased temperature. The analysis indicates that all enzyme activities in the system are affected and that the shapes of the time trends in activities depend on the fatty-acyl CoA chain lengths of the different ceramide species in the system.

No MeSH data available.


Related in: MedlinePlus