Compositions and methods for modeling human metabolism

Abstract

The present invention provides Homo sapiens Recon 1, a manually assembled, functionally validated, bottom-up reconstruction of human metabolism. Recon 1's 1496 genes, 2004 proteins, 2766 metabolites, and 3311 biochemical and transport reactions were extracted from more than 50 years of legacy biochemical knowledge and Build 35 of the human genome sequence.

1 . A computer readable medium comprising:
 (a) a data structure relating a plurality of  H. sapiens  reactants to a plurality of  H. sapiens  reactions, wherein each of the  H. sapiens  reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction, and a stoichiometric coefficient relating the substrate and the product, wherein at least one of the  H. sapiens  reactions is annotated to indicate an associated gene in Table 4;   (b) a gene database comprising information characterizing the associated gene;   (c) a constraint set for the plurality of  H. sapiens  reactions; and   (d) commands for determining at least one flux distribution that minimizes or maximizes an objective function when the constraint set is applied to the data structure, wherein the at least one flux distribution is predictive of a  H. sapiens  physiological function,   
       wherein the data structure comprises Tables 1, 4, 5, 7 and 8. 
     
     
         2 . The computer readable medium of  claim 1 , wherein at least one reactant in the plurality of  H. sapiens  reactants or at least one reaction in the plurality of  H. sapiens  reactions is annotated with an assignment to one or more subsystems or compartments. 
     
     
         3 . The computer readable medium of  claim 1 , wherein the plurality of reactions comprises at least one reaction from a  H. sapiens  metabolic network. 
     
     
         4 . The computer readable medium of  claim 3 , wherein the  H. sapiens  metabolic network is selected from the group consisting of amino acid metabolism, carbohydrate metabolism, energy metabolism, glycan metabolism, lipid metabolism, nucleotide metabolism, xenobiotic metabolism, vitamin metabolism and cofactor metabolism. 
     
     
         5 . The computer readable medium of  claim 1 , wherein the  H. sapiens  physiological function is selected from the group consisting of growth, energy production, redox equivalent production, biomass production, production of biomass precursors, production of a protein, production of an amino acid, production of a purine, production of a pyrimidine, production of a lipid, production of a fatty acid, production of a cofactor, production of a hormone, production of a bioactive small molecule, production of a cell wall component, transport of a metabolite, and consumption of carbon, nitrogen, sulfur, phosphate, hydrogen or oxygen. 
     
     
         6 . The computer readable medium of  claim 1 , wherein the  H. sapiens  physiological function is selected from the group consisting of degradation of a protein, degradation of an amino acid, degradation of a purine, degradation of a pyrimidine, degradation of a lipid, degradation of a fatty acid, degradation of a cofactor and degradation of a cell wall component. 
     
     
         7 . The computer readable medium of  claim 1 , wherein the data structure comprises a set of linear algebraic equations. 
     
     
         8 . The computer readable medium of  claim 1 , wherein the data structure comprises a matrix. 
     
     
         9 . The computer readable medium of  claim 1 , wherein the commands comprise an optimization problem. 
     
     
         10 . The computer readable medium of  claim 1 , wherein the commands comprise a linear program. 
     
     
         11 . The computer readable medium of  claim 2 , wherein a first substrate or product in the plurality of  H. sapiens  reactions is assigned to a first compartment and a second substrate or product in the plurality of  H. sapiens  reactions is assigned to a second compartment. 
     
     
         12 . The computer readable medium of  claim 1 , wherein a plurality of the  H. sapiens  reactions is annotated to indicate a plurality of associated genes and wherein the gene database comprises information characterizing the plurality of associated genes. 
     
     
         13 . A computer readable medium comprising:
 (a) a data structure relating a plurality of  H. sapiens  reactants to a plurality of  H. sapiens  reactions, wherein each of the  H. sapiens  reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;   (b) a constraint set for the plurality of  H. sapiens  reactions; and   (c) commands for determining at least one flux distribution that minimizes or maximizes an objective function when the constraint set is applied to the data representation, wherein the at least one flux distribution is predictive of  H. sapiens  cellular growth,   
       wherein the data structure comprises Tables 1, 4, 5, 7 and 8. 
     
     
         14 . A method for predicting a  H. sapiens  physiological function comprising:
 (a) providing a data structure relating a plurality of  H. sapiens  reactants to a plurality of reactions, wherein each of the  H. sapiens  reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;   (b) providing a constraint set for the plurality of  H. sapiens  reactions;   (c) providing an objective function; and   (d) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, thereby predicting a  H. sapiens  physiological function related to the gene, wherein the data structure comprises Tables 1, 4, 5, 7 and 8.   
     
     
         15 . The method of  claim 14 , wherein at least one of the  H. sapiens  reactions is annotated to indicate an associated gene 
     
     
         16 . The method of  claim 14 , wherein the plurality of  H. sapiens  reactions comprises at least one reaction from a  H. sapiens  metabolic network. 
     
     
         17 . The method of  claim 16 , wherein the  H. sapiens  metabolic network is selected from the group consisting of amino acid metabolism, carbohydrate metabolism, energy metabolism, glycan metabolism, lipid metabolism, nucleotide metabolism, xenobiotic metabolism, vitamin metabolism and cofactor metabolism. 
     
     
         18 . The method of  claim 14 , wherein the  H. sapiens  physiological function is selected from the group consisting of growth, energy production, redox equivalent production, biomass production, production of biomass precursors, production of a protein, production of an amino acid, production of a purine, production of a pyrimidine, production of a lipid, production of a fatty acid, production of a cofactor, production of a hormone, production of a bioactive small molecule, production of a cell wall component, transport of a metabolite, and consumption of carbon, nitrogen, sulfur, phosphate, hydrogen or oxygen. 
     
     
         19 . The method of  claim 14 , wherein the  H. sapiens  physiological function is selected from the group consisting of glycolysis, the TCA cycle, pentose phosphate pathway, respiration, biosynthesis of an amino acid, degradation of an amino acid, biosynthesis of a purine, biosynthesis of a pyrimidine, biosynthesis of a lipid, metabolism of a fatty acid, biosynthesis of a cofactor, metabolism of a cell wall component, transport of a metabolite and metabolism of a carbon source, nitrogen source, oxygen source, phosphate source, hydrogen source or sulfur source. 
     
     
         20 . The method of  claim 14 , wherein the data structure comprises a set of linear algebraic equations. 
     
     
         21 . The method of  claim 14 , wherein the data structure comprises a matrix. 
     
     
         22 . The method of  claim 14 , wherein the flux distribution is determined by linear programming. 
     
     
         23 . The method of  claim 14 , further comprising:
 (e) providing a modified data structure, wherein the modified data structure comprises at least one added reaction, compared to the data structure of part (a); and   (f) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the modified data structure, thereby predicting a  H. sapiens  physiological function.   
     
     
         24 . The method of  claim 23 , further comprising identifying at least one participant in the at least one added reaction. 
     
     
         25 . The method of  claim 24 , wherein the identifying at least one participant comprises associating a  H. sapiens  protein with the at least one reaction. 
     
     
         26 . The method of  claim 25 , further comprising identifying at least one gene that encodes the protein. 
     
     
         27 . The method of  claim 24 , further comprising identifying at least one compound that alters the activity or amount of the at least one participant, thereby identifying a candidate drug or agent that alters a  H. sapiens  physiological function. 
     
     
         28 . The method of  claim 14 , further comprising:
 (e) providing a modified data structure, wherein the modified data structure lacks at least one reaction compared to the data structure of part (a); and   (f) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the modified data structure, thereby predicting a  H. sapiens  physiological function.   
     
     
         29 . The method of  claim 28 , further comprising identifying at least one participant in the at least one reaction. 
     
     
         30 . The method of  claim 29 , wherein the identifying at least one participant comprises associating a  H. sapiens  protein with the at least one reaction. 
     
     
         31 . The method of  claim 30 , further comprising identifying at least one gene that encodes the protein that performs the at least one reaction. 
     
     
         32 . The method of  claim 29 , further comprising identifying at least one compound that alters the activity or amount of the at least one participant, thereby identifying a candidate drug or agent that alters a  H. sapiens  physiological function. 
     
     
         33 . The method of  claim 14 , further comprising:
 (e) providing a modified constraint set, wherein the modified constraint set comprises a changed constraint for at least one reaction compared to the constraint for the at least one reaction in the data structure of part (a); and   determining at least one flux distribution that minimizes or maximizes the objective function when the modified constraint set is applied to the data structure, thereby predicting a  H. sapiens  physiological function.   
     
     
         34 . The method of  claim 33 , further comprising identifying at least one participant in the at least one reaction. 
     
     
         35 . The method of  claim 34 , wherein the identifying at least one participant comprises associating a  H. sapiens  protein with the at least one reaction. 
     
     
         36 . The method of  claim 35 , further comprising identifying at least one gene that encodes the protein. 
     
     
         37 . The method of  claim 34 , further comprising identifying at least one compound that alters the activity or amount of the at least one participant, thereby identifying a candidate drug or agent that alters a  H. sapiens  physiological function. 
     
     
         38 . The method of  claim 14 , further comprising providing a gene database relating one or more reactions in the data structure with one or more human genes or proteins. 
     
     
         39 . A method for predicting human cellular growth comprising:
 (a) providing a data structure relating a plurality of  H. sapiens  reactants to a plurality of  H. sapiens  reactions, wherein each of the  H. sapiens  reactions comprises one or more reactants identified as a substrate of the reaction, one or more reactants identified as a product of the reaction and a stoichiometric coefficient relating the substrate and the product;   (b) providing a constraint set for the plurality of  H. sapiens  reactions;   (c) providing an objective function; and   (d) determining at least one flux distribution that minimizes or maximizes the objective function when the constraint set is applied to the data structure, thereby predicting human cellular growth,   
       wherein the data structure comprises Tables 1, 4, 5, 7 and 8.