TY - JOUR

T1 - Network-based analysis of metabolic regulation in the human red blood cell

AU - Price, Nathan D.

AU - Reed, Jennifer L.

AU - Papin, Jason A.

AU - Wiback, Sharon J.

AU - Palsson, Bernhard O.

N1 - Funding Information:
The authors would like to thank Iman Famili and Dr. Radhakrishnan Mahadevan for insightful discussions, as well as Natalie Duarte for helpful feedback on this manuscript. We would like to acknowledge the support of the NIH (GM 57089) and the Whitaker Foundation (Graduate Research Fellowship to JP).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2003/11/21

Y1 - 2003/11/21

N2 - Reconstruction of cell-scale metabolic networks is now possible. A description of allowable metabolic network functions can be obtained using extreme pathways, which are the convex basis vectors of the solution space containing all steady state flux distributions. However, only a portion of these allowable network functions are physiologically possible due to kinetic and regulatory constraints. Methods are now needed that enable us to take a defined metabolic network and deduce candidate regulatory structures that control the selection of these physiologically relevant states. One such approach is the singular value decomposition (SVD) of extreme pathway matrices (P), which allows for the characterization of steady state solution spaces. Eigenpathways, which are the left singular vectors from the SVD of P, can be described and categorized by their biochemical function. SVD of P for the human red blood cell showed that the first five eigenpathways, out of a total of 23, effectively characterize all the relevant physiological states of red blood cell metabolism calculated with a detailed kinetic model. Thus, with five degrees of freedom the magnitude and nature of the regulatory needs are defined. Additionally, the dominant features of these first five eigenpathways described key metabolic splits that are indeed regulated in the human red blood cell. The extreme pathway matrix is derived directly from network topology and only knowledge of Vmax values is needed to reach these conclusions. Thus, we have implemented a network-based analysis of regulation that complements the study of individual regulatory events. This topological approach may provide candidate regulatory structures for metabolic networks with known stoichiometry but poorly characterized regulation.

AB - Reconstruction of cell-scale metabolic networks is now possible. A description of allowable metabolic network functions can be obtained using extreme pathways, which are the convex basis vectors of the solution space containing all steady state flux distributions. However, only a portion of these allowable network functions are physiologically possible due to kinetic and regulatory constraints. Methods are now needed that enable us to take a defined metabolic network and deduce candidate regulatory structures that control the selection of these physiologically relevant states. One such approach is the singular value decomposition (SVD) of extreme pathway matrices (P), which allows for the characterization of steady state solution spaces. Eigenpathways, which are the left singular vectors from the SVD of P, can be described and categorized by their biochemical function. SVD of P for the human red blood cell showed that the first five eigenpathways, out of a total of 23, effectively characterize all the relevant physiological states of red blood cell metabolism calculated with a detailed kinetic model. Thus, with five degrees of freedom the magnitude and nature of the regulatory needs are defined. Additionally, the dominant features of these first five eigenpathways described key metabolic splits that are indeed regulated in the human red blood cell. The extreme pathway matrix is derived directly from network topology and only knowledge of Vmax values is needed to reach these conclusions. Thus, we have implemented a network-based analysis of regulation that complements the study of individual regulatory events. This topological approach may provide candidate regulatory structures for metabolic networks with known stoichiometry but poorly characterized regulation.

KW - Constraint-based models

KW - Elementary modes

KW - Extreme pathways

KW - SVD

KW - Singular value decomposition

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U2 - 10.1016/S0022-5193(03)00237-6

DO - 10.1016/S0022-5193(03)00237-6

M3 - Article

C2 - 14575652

AN - SCOPUS:0142186707

VL - 225

SP - 185

EP - 194

JO - Journal of Theoretical Biology

JF - Journal of Theoretical Biology

SN - 0022-5193

IS - 2

ER -