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Exploring the competitive dynamic enzyme allocation scheme through enzyme cost minimization.

ABSTRACT: Enzyme allocation (or synthesis) is a crucial microbial trait that mediates soil biogeochemical cycles and their responses to climate change. However, few microbial ecological models address this trait, particularly concerning multiple enzyme functional groups that regulate complex biogeochemical processes. Here, we aim to fill this gap by developing a COmpetitive Dynamic Enzyme ALlocation (CODEAL) scheme for six enzyme groups that act as indicators of inorganic nitrogen (N) transformations in the Microbial-ENzyme Decomposition (MEND) model. This allocation scheme employs time-variant allocation coefficients for each enzyme group, fostering mutual competition among the multiple groups. We show that the principle of enzyme cost minimization is achieved by using the substrate's saturation level as the factor for enzyme allocation, resulting in an enzyme-efficient pathway with minimal enzyme cost per unit metabolic flux. It suggests that the relative substrate availability affects the trade-off between enzyme production and metabolic flux. Our research has the potential to give insights into the nuanced dynamics of the N cycle and inspire the evolving landscape of enzyme-mediated biogeochemical processes in microbial ecological modeling, which is gaining increasing attention.

SUBMITTER: Qi S

PROVIDER: S-EPMC10662282 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Exploring the competitive dynamic enzyme allocation scheme through enzyme cost minimization.

Qi Shanshan S Wang Gangsheng G Li Wanyu W Zhou Shuhao S

ISME communications 20231120 1

Enzyme allocation (or synthesis) is a crucial microbial trait that mediates soil biogeochemical cycles and their responses to climate change. However, few microbial ecological models address this trait, particularly concerning multiple enzyme functional groups that regulate complex biogeochemical processes. Here, we aim to fill this gap by developing a COmpetitive Dynamic Enzyme ALlocation (CODEAL) scheme for six enzyme groups that act as indicators of inorganic nitrogen (N) transformations in t ...[more]

PMID: 37985704

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Project description:Early-stage breast cancer patients comprise a large proportion of patients treated with radiotherapy in Canada. Proponents have suggested that five-fraction hypofractionated radiotherapy for these patients would result in significant cost savings. An assessment of this argument is thus warranted. The FAST-Forward and UK FAST clinical trials each demonstrated that their respective hypofractionated regimens provided equivalent outcomes compared with standard regimens. Thus, a cost-minimization analysis was performed to quantify the potential savings associated with these regimens, which were designated as FAST-Forward 1 (26 Gy/5 fractions/1 week) and FAST-Forward 2 (27 Gy/5 fractions/1 week), and UK FAST 1 (28.5 Gy/5 fractions/5 weeks) and UK FAST 2 (30 Gy/5 fractions/5 weeks). A standard regimen of 42.5 Gy/16 fractions/5 weeks was also included. A comprehensive model of radiotherapy costs for a Canadian cancer centre was created. Time, labour costs, and capital costs were calculated for each regimen and applied using established measures. The total costs per patient for the FAST-Forward trials were $851.77 for FAST-Forward 1 and $874.77 for FAST-Forward 2, providing a total savings of $487.99 and $464.99, respectively. Similarly, the total costs per patient for the FAST trials were $979.75 for UK FAST 1 and $1017.70 for UK FAST 2, providing savings of $360.01 and $322.06, respectively. Following the FAST-Forward 1 regimen results in the greatest reduction of infrastructure and human resources costs at 36.42% compared with the standard. Sensitivity analysis shows a maximum per-patient costs savings ranging from $474.60 to $508.53 for the FAST-Forward 1 trial, which translates to an annual savings of $174,700/year locally and $2.06 million/year province-wide, based on a moderate-to-large size department workload. Compared with a standard radiotherapy regimen, all FAST-Forward and UK FAST hypofractionated regimens provide cost savings for the treatment of early-stage breast cancer. The cost savings associated with each of these equivalent regimens can be directly calculated; activities in this model can easily be adjusted to account for cost variations, allowing other centres to calculate cost impacts specific to their own centres.

Project description:BackgroundArgentina currently uses a pentavalent vaccine containing diphtheria, tetanus, pertussis (whole cell), Haemophilus influenza type b and hepatitis B antigens, administered concomitantly with the inactivated polio vaccine (IPV) (DTwP-Hib-HB plus IPV) in its childhood vaccination schedule. However, hexavalent vaccines containing acellular pertussis antigens (DTaP-Hib-HB-IPV) and providing protection against the same diseases are also licensed, but are only available with a private prescription or for high-risk pre-term infants in the public health program. We analyzed the cost of switching from the current schedule to the alternative schedule with the hexavalent vaccine in Argentina, assuming similar levels of effectiveness.MethodsThe study population was infants ≤ 1 year of age born in Argentina from 2015 to 2019. The analysis considered adverse events, programmatic, logistic, and vaccine costs of both schemes from the societal perspective. The societal costs were disaggregated to summarize costs incurred in the public sector and with vaccination pre-term infants in the public sector. Costs were expressed in 2021 US Dollars (US$).ResultsAlthough the cost of vaccines with the alternative scheme would be US$39.8 million (M) more than with the current scheme, these additional costs are in large part offset by fewer adverse event-associated costs and lower programmatic costs such that the overall cost of the alternative scheme would only be an additional US$3.6 M from the societal perspective. The additional cost associated with switching to the alternative scheme in the public sector and with the vaccination of pre-term infants in the public sector would be US$2.1 M and US$84,023, respectively.ConclusionsThe switch to an alternative scheme with the hexavalent vaccine in Argentina would result in marginally higher vaccine costs, which are mostly offset by the lower costs associated with improved logistics, fewer separate vaccines, and a reduction in adverse events.

Project description:Bacterial growth depends crucially on metabolic fluxes, which are limited by the cell's capacity to maintain metabolic enzymes. The necessary enzyme amount per unit flux is a major determinant of metabolic strategies both in evolution and bioengineering. It depends on enzyme parameters (such as kcat and KM constants), but also on metabolite concentrations. Moreover, similar amounts of different enzymes might incur different costs for the cell, depending on enzyme-specific properties such as protein size and half-life. Here, we developed enzyme cost minimization (ECM), a scalable method for computing enzyme amounts that support a given metabolic flux at a minimal protein cost. The complex interplay of enzyme and metabolite concentrations, e.g. through thermodynamic driving forces and enzyme saturation, would make it hard to solve this optimization problem directly. By treating enzyme cost as a function of metabolite levels, we formulated ECM as a numerically tractable, convex optimization problem. Its tiered approach allows for building models at different levels of detail, depending on the amount of available data. Validating our method with measured metabolite and protein levels in E. coli central metabolism, we found typical prediction fold errors of 4.1 and 2.6, respectively, for the two kinds of data. This result from the cost-optimized metabolic state is significantly better than randomly sampled metabolite profiles, supporting the hypothesis that enzyme cost is important for the fitness of E. coli. ECM can be used to predict enzyme levels and protein cost in natural and engineered pathways, and could be a valuable computational tool to assist metabolic engineering projects. Furthermore, it establishes a direct connection between protein cost and thermodynamics, and provides a physically plausible and computationally tractable way to include enzyme kinetics into constraint-based metabolic models, where kinetics have usually been ignored or oversimplified.

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Exploring the competitive dynamic enzyme allocation scheme through enzyme cost minimization.

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Exploring the competitive dynamic enzyme allocation scheme through enzyme cost minimization.

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