CN108021787A - A kind of method that dynamic metabolism network is built according to elementary reaction topological structure - Google Patents
A kind of method that dynamic metabolism network is built according to elementary reaction topological structure Download PDFInfo
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Abstract
The invention discloses a kind of dynamic metabolism network construction method, it includes step (a) for the dynamic metabolism network to be built, finds out all isolated reactions and regulation and control are reacted, determine the elementary reaction speed constant number of redundancy in each isolated reaction；(b) measure by experiment in vitro or obtain the michaelis-Menton kinetics parameter that all isolated reactions and regulation and control are reacted from existing zymetology database；(c/d) in each isolated reaction and regulation and control reaction, the absolute value and/or relative value of all the remaining elementary reaction speed constants are calculated；(e) the elementary reaction speed constant obtained using step (c) and (d), elementary reaction topological structure type dynamic metabolism network is built by computer.The method of the present invention without deriving michaelis-Menton kinetics class rate equation analytic expression one by one, and on the premise of having thermodynamic equilibrium constant, the involved elementary reaction speed constant of acquisition regulation and control reaction is fairly simple, is suitable for computer and builds large-scale metabolism network.
Description
Technical field
The invention belongs to enzyme kinetics field, and in particular to a kind of to build dynamic generation according to elementary reaction topological structure
The method for thanking to network.
Background technology
The model of existing description metabolism network is broadly divided into two kinds：1) Chemical Measurement based on network topology structure
Model (O'Brien, E.J.et al., Cell, 2015:161,971-987；Schuster et al.,Nature
Biotechnology,2000:18,326-332)；2) the dynamic generation of metabolite concentration, enzyme amount and Metabolism regulation effect is introduced
Thank to network model (Khodayari, A.et al., Metabolic Engineering.2014,25:50-62).The former pertains only to
Metabolic fluxes (i.e. reaction speed), method is simple, but Limited information；The latter is more comprehensive, but it is a huge to obtain model parameter
Challenge.
On dynamic Metabolic Network Model, relative to experience or semiempirical rate equation, only michaelis-Menton kinetics class speed
Equation is theoretical property kinetic formulation.Michaelis-Menton kinetics rate equation is needed, and (a) carries out stable state to enzyme intermediate
Assuming that or Fast-Balance is made to some elementary reaction it is assumed that (b) utilizes the law of mass action of elementary reaction, to elementary reaction ginseng
Number is integrated, and obtains metabolite concentration and the analytic expression of parameter, and then obtains serial rate equation, and classical Michaelis-Menten equation is just
It is typical example.Parameter (such as k of michaelis-Menton kinetics classcat,KmS,KmpDeng) can be measured by experiment in vitro reaction rate
Arrive, and elementary reaction speed constant (ki) then generally cannot.Some professional zymetology data (such as BRENDA, SABIO-RK etc.)
The michaelis-Menton kinetics class parameter of decades measuring is arranged and included.Built using michaelis-Menton kinetics class rate equation
Dynamic network, it is very not difficult for being handled as single enzyme reaction, but the reaction in metabolism network often introduces
Interaction (such as regulation and control reaction) between effector and enzyme, this process becomes increasingly complex (not has solution sometimes
Analysis formula), and be not easy computer and automatically process.
The content of the invention
, can it is an object of the invention to propose a kind of new method that metabolism network is built according to elementary reaction topological structure
To determine that the primitive that all enzyme reactions are related in metabolism network is anti-by single vitro reactions (i.e. isolated reaction) rate experiments
Answer speed constant, with overcome elementary reaction speed constant excessive and can not complete measuring the problem of.
Elementary reaction topological structure only has a kind of form of the law of mass action, as long as network structure and internal regulation effect
Properly and there is its kinetic parameter, the building process of whole network can be completed by machine completely, so that large-scale to build
Dynamic metabolism network provides new method.
The dynamic metabolism network construction method of the present invention, comprises the following steps：
(a) for the dynamic metabolism network to be built, all isolated reactions and regulation and control reaction and the Michaelis being related to are found out
Kinetic parameter and elementary reaction speed constant, determine the independent power parameter number of each isolated reaction and regulation and control reaction
Mesh, and then determine the elementary reaction speed constant number of redundancy in each isolated reaction；Wherein, each isolated reaction and tune
The elementary reaction speed constant number of redundancy is respectively that the elementary reaction speed constant that it is related to is total with independently moving in control reaction
The difference of mechanics parameter number；
(b) measure by experiment in vitro or obtain the rice that all isolated reactions and regulation and control are reacted from existing zymetology database
Family name's kinetic parameter；
(c) in each isolated reaction, using the michaelis-Menton kinetics parameter of step (b) acquisition, to the elementary reaction of redundancy
Speed constant assignment is set to fixed constant, with reference to the relation between michaelis-Menton kinetics parameter and elementary reaction speed constant,
Calculate the absolute value or relative value of remaining all elementary reaction speed constant that isolated reaction is related to；
(d) in each regulation and control reaction, using the michaelis-Menton kinetics parameter of step (b) acquisition, to the elementary reaction of redundancy
Speed constant assignment is set to fixed constant, with reference to the relation between michaelis-Menton kinetics parameter and elementary reaction speed constant,
Calculate the relative value of remaining all elementary reaction speed constant that regulation and control reaction is related to；
(e) the elementary reaction speed constant obtained using step (c) and (d), elementary reaction topology is built by computer
Structural type dynamic metabolism network.
In step (e), elementary reaction topological structure type dynamic metabolism network includes the compound of each metabolin and enzyme
Elementary reaction rate equation and enzyme amount constraints.As a kind of general method, elementary reaction topological dynamics structure
Metabolism network needs to write elementary reaction rate equation to the compound of each metabolin (including substrate and product) and enzyme, and
All free enzyme concentrations are eliminated using enzyme amount constraints, then utilize software (such as odefun functions of MATLAB), you can
Obtain the performance graph of all metabolite concentrations.
With the demonstration mode metabolism network shown in following formula A, (network spontaneous can not reach metabolic homeostasis, so right and wrong below
Illustrate the structure of the elementary reaction topological structure type dynamic metabolism network of the present invention exemplified by really), formula B show the demonstration mode
The substep elementary reaction of metabolism network.
Being directed to 2 enzymes, (enzyme amount concentration is respectively e0,1And e0,2), including 2 isolated reaction (i.e. single substrate mono-product species
Reversible reaction v1With the double product irreversible reaction v of Double bottom thing2) and 2 regulation and control reaction (i.e. v3And v4).This network shares 6
" metabolin " (i.e. S1, S2, S3, P1, P2, P3), compound (the i.e. E of 6 enzymes1S1, E1P2, E2S2, E2P1, E2P3And E2S2S3), and 2
A free enzyme (i.e. E1And E2).Enzyme amount e0,1And e0,2For constraints, can be used to eliminate 2 free enzyme concentration (E1) and (E2)。
For above-mentioned demonstration mode metabolism network, elementary reaction topological dynamics (equation (1)) is by following 12 ordinary differential sides
Journey forms (ODE number is the sum of metabolin and multienzyme complex quantity)：
2 restriction relations can be used to eliminate the free enzyme concentration (E in equation (1) below1) and (E2)：
e0,1=(E1)+(E1S1)+(E1P2) (2-1)
e0,2=(E2)+(E2S2)+(E2P3)+(E2P1)+(E2S2S3) (2-2)
Build above-mentioned metabolism network, it is thus necessary to determine that each elementary reaction speed constant, and in the present invention, elementary reaction speed is normal
Number is determined by step (a)~(d).
Contrast elementary reaction topological structure, and the rice using michaelis-Menton kinetics parameter and elementary reaction speed constant as parameter
Family name's kinetic rate equation analytic expression, its elementary reaction speed constant is identical.We can be surveyed by experiment in vitro
Independent michaelis-Menton kinetics parameter fixed or that all isolated reactions and regulation and control reaction are obtained from existing zymetology database, to redundancy
Elementary reaction speed constant assignment is set to fixed constant, joins further according to elementary reaction speed constant and independent michaelis-Menton kinetics
Relation between number can calculate the absolute value or relative value of the elementary reaction speed constant of related to isolated reaction, and
Relate to the relative value of the elementary reaction speed constant of regulation and control reaction；Then in conjunction with elementary reaction topological dynamics equation and matter
Amount conservation constraints relation can build elementary reaction topological structure type dynamic metabolism network.
In step (a), each isolated reaction has its corresponding elementary reaction speed constant and number, such as enzyme with regulation and control reaction
Single substrate mono-product species irreversible reaction of catalysis has 3 elementary reaction speed constants, and single substrate mono-product species of enzymatic can be converse
There should be 4 elementary reaction speed constants, the double product irreversible reactions of Double bottom thing of enzymatic have 6 elementary reaction speed constants,
The double product reversible reactions of Double bottom thing of enzymatic have 8 elementary reaction speed constants, and regulating and controlling reaction has two elementary reaction speed
Rate constant.
For each isolated reaction and regulation and control react, although be between all elementary reaction speed constants it is mutually independent,
But when solution is using michaelis-Menton kinetics rate equation of all elementary reaction speed constants as parameter, some or a other parameter can
To be considered as constant, the fact that illustrate some or a other parameter redundancy.This is a kind of extremely special parameter redundancy,
We are called the kinetic parameter (Redundant kinetic parameter, be abbreviated as RKP) of redundancy, hereinafter referred to as superfluous
Remaining parameter.And remaining certain number of elementary reaction speed constant is mutually independent, the primitive of this part independence when solving
Reaction rate constant is also known as independent power parameter (Independent Kinetic Parameter, IKP).
Likewise, using michaelis-Menton kinetics parameter as in the michaelis-Menton kinetics rate equation analytic expression of parameter, there is also above-mentioned
Point of independent power parameter and nuisance parameter.And either with michaelis-Menton kinetics parameter still with elementary reaction speed constant
For the michaelis-Menton kinetics rate equation analytic expression of parameter, independent power number of parameters therein is constant, not with using
Parameter type changes and changes.
Therefore preferably, determining the independent power number of parameters of each isolated reaction and regulation and control reaction in step (a)
Concretely comprise the following steps：First according to respectively by michaelis-Menton kinetics parameter and elementary reaction speed constant be the rice in the form of two kinds of parameter
Family name's kinetic rate equation analytic expression, and michaelis-Menton kinetics rate equation analytic expression have the restrictive condition of finite solution, pass through
Mathematical simulation determines the independent power number of parameters in each isolated reaction and regulation and control reaction.
On how to determine independent power number of parameters, how to determine in other words redundancy elementary reaction speed constant and
Its number, below with the double product reversible reactions (i.e. Bi-Bi Ping Pong reversible reactions) of the Double bottom thing of enzymatic and enzymatic
Single substrate mono-product species irreversible reaction (i.e. Uni-Uni irreversible reactions) exemplified by illustrate, further explain how at the same time
Elementary reaction speed constant is solved using michaelis-Menton kinetics parameter.
1st, Bi-Bi Ping Pong reversible reactions
It can be made of following elementary reaction group (or topological structure),
Wherein S1And S2For substrate, P1And P2For product, E and E ' are free enzyme, ES1With E ' S2For 2 compounds of enzyme, k1
~k4And k-1~k-4For 8 elementary reaction speed constants.
The reaction one shares 10 michaelis-Menton kinetics parameters, is referred to as M-M parameters, shares 2 classes.First kind parameter is catalysis
Constant kcat(as being reversible reaction, then haveWith) and Michaelis constant Km(for the double product reversible reactions of Double bottom thing, then have).Second class parameter proposes (Cleland, W.W., Biochimica et by Cleland
Biophysica Acta 1963:67,104-137), it is usually the inhibition constant K of enzymei(can be converse for the double products of Double bottom thing
Should, then may have).In michaelis-Menton kinetics rate equation analytic expression, first kind parameter must be whole
Use, in the case where first kind parameter is inadequate, the second class parameter just can be used；Dependent is there may exist in second class parameter
Parameter.Bi-Bi Ping Pong reversible reactions have 6 first kind M-M parameters (i.e.
Second class totally 4 (be typically inhibition constant) is,
As isolated reaction, the rate equation analytic expression v of Bi-Bi Ping Pong reversible reactions, which can be expressed, to be become,
Alternatively,
Equation (4-1) and equation (4-2) can be known as michaelis-Menton kinetics rate equation, but what equation (4-1) used
Parameter is elementary reaction rate constants ki(i.e. all 8 ki), and the parameter that equation (4-2) uses is M-M parameter [the i.e. first kind
's In the second classWith(totally 8)].
This reaction pertains only to 8 mutually independent elementary reaction speed constant (i.e. k1, k2, k3, k4, k5, k6, k7, k8),
So independent parameter number IKPN≤8.(redefined and simple however, equation (3-1) and (3-2) define 10 M-M parameters altogether
Turn to M1, M2, M3, M4, M5, M6, M7, M8, M9, M10), so certainly existing at least two constraints pass between this 10 M-M parameters
System, i.e., at least two M-M parameters are not independent.Since 6 M-M parameters in equation (3-1) must be used to being forced property
Make independent M-M parameters, therefore IKPN≤6.Accordingly, 6≤IKPN≤8, share 3 kinds possible (i.e. IKPN=6 ,=7 and=8).
As algebraical axiom, the equation group of n unknown quantity to be solved is, it is necessary to n independent and compatible equations.Such as
At least one in n equation of fruit is not independent, then solution of the equation group in the presence of no array.If at least one in n equation
To being incompatible, then equation group is without solution.If all equations in equation group are all linear, there is the situation of solution
Under, its solution must be unique.Even if there is nonlinear equation in equation group, on the premise of no unique solution, it is also possible to there are thing
Manage limited group of solution of meaning.
The first step of IKPN is determined as demonstration, we first assume IKPN=8.Should so there are 8 kiCan be independent by 8
MiSolve.Such as by M1, M2, M3, M4, M5, M6, M7And M8Equation group (5.1) is formed, i.e.,
In this way, it is introduced into the M of equation group9And M10Then certainly not independent M-M parameters, itself and kiRelational expression be,
M9=f9(k1, k2, k3, k4, k5, k6, k7, k8), M10=f10(k1, k2, k3, k4, k5, k6, k7, k8) (5-2)
Due to 6 M in equation (3-1)iAny 2 in equation (5-2) must be so selected as independent M-M parameters
A MiShare 6 kinds of possibilities (i.e.).8 M-M parameters are regarded as known quantity, 8 kiFor unknown quantity, gained solution is (if deposited
) there is following form certainly,
Using equation (5.1), 2 not independent Mie scattering parameter M9And M10Following form can be characterized as,
Solved using the solve functions of MATLAB, as n=8,8 equations of the above can not obtain unique solution or finite solution.
It can thus be appreciated that IKPN ≠ 8.
The second step of IKPN is determined as demonstration, it will be assumed that n=7.Select 7 MiAs known quantity, then select 7 kiAs
Unknown quantity [remaining ki(that demonstrate here is k8) is used as a constant], using 7 equations composition Nonlinear System of Equations [i.e.
Use 6 M in equation (3-1)iWith 1 M in equation (3-2)i]。
3 M not usedi(the not independent M-M parameters of 3 attempted) and its and kiRelational expression is,
In equation group (7-1), M1... M7And k1... k7It should be independent model parameter, M8, M9And M10It should be not only
Vertical M-M parameters.If M8, M9And M10Really it is not independent, then the arbitrary constant k in equation (7-2)8≡ C will disappear (i.e. with
Under equation (7-4)].With M8, M9And M10Difference, k8Independently of k1... k7In any one ki, it is impossible to have similar
The parameter of equation (7-4) relies on form.In the case where equation (7-1) has unique or finite solution, it is clear that k8No longer it has been one
Model parameter, but an arbitrary constant being totally independent of outside model.Reacted for Bi-Bi Ping Pong, with top
Journey group (7-1) existence and unique solution, illustrates IKPN=7.Such one group of unique solution has following forms,
Due to M1, M2, M3, M4, M5, M6, M77 independent power parameters can be used as, 3 do not appear in above equation group
Middle Mi then can be completely and independently by this 7 MiFollowing form is expressed as,
For Bi-Bi Ping Pong reversible reaction equations, a kind of concrete form of equation (7-4) is,
Although 8 kiBetween be mutually independent, but the k when solving equation (7-1)8The fact that can be considered as constant, explanation
k8Redundancy.This is a kind of extremely special parameter redundancy, we are called the kinetic parameter (Redundant of redundancy
Kinetic parameter, are abbreviated as RKP).
The facture of equation (7-1) proves, 8 kiIn there is one redundancy (RKP occur) occur.With k-4It is (k for RKP-4
≡C1), other kiIt can be obtained by independent Mie scattering parameter.Reacted for Bi-Bi Ping Pong, remaining 7 kiIt can be determined
For,
For example artificially give k-4≡C1=10-6, the 7 independent Mie scattering parameters obtained using measuring are (i.e. ), all 8 elementary reaction rate constants ksiThus it is confirmed as,
k-4=10-6 (9-8)
2nd, Uni-Uni irreversible reactions
Elementary reaction formula is as follows：
Wherein, S is substrate, E is enzyme, ES is the compound of enzyme, P is product；k1、k2And k3Join for elementary reaction kinetics
Number；Michaelis-Menton kinetics parameter includes Michaelis constant KmWith catalytic constant kcat；k1、k2、k3And Km、kcatThere are following correlation,
Enzyme reaction speed, e are represented with voRepresent the total concentration of enzyme E, [S] represents the concentration of substrate S；Assume in quasi-stable state
Under, following elementary reaction kinetics equation is calculated,
Substitute into KmAnd kcatFollowing michaelis-Menton kinetics equation is obtained,
The number that definite independent michaelis-Menton kinetics parameter is calculated by simulating is 2；So independent elementary reaction speed
Constant number also be 2, and then understand redundancy elementary reaction speed constant number be 1.
Michaelis constant K can be measured by experiment in vitromWith catalytic constant kcat；By kcat=k2Directly solve independent primitive
Reactive kinetics parameters k2；And k1And k—1In have one for dependent, and another is independent, if being made with any of which
For dependent elementary reaction speed constant assign arbitrarily on the occasion of, then with k2Be updated in the lump after constraint equation solve obtain it is another
A elementary reaction kinetics parameter.
It is independent for the relation between the michaelis-Menton kinetics parameter and elementary reaction speed constant of other types independent reaction
Kinetic parameter number, and how by michaelis-Menton kinetics parametric solution elementary reaction speed constant, method is identical, herein no longer
Repeat.
And reacted for regulation and control, any one regulation and control reaction has the product of terminal, in the case where there is metabolic homeostasis,
It must be zero that it, which reacts flux, that is, reach thermodynamical equilibrium, and the independent power number of parameters of each regulation and control reaction is 1, is adjusted
The thermodynamic equilibrium constant of control reaction is michaelis-Menton kinetics parameter.Reacted with the regulation and control in formula (B) for v3And v4Exemplified by, its base
Elementary reaction formula is：
For E1And E2Regulation and control reaction, as long as obtaining E from database1With P2, E2With P1With reference to the equilibrium constant Therefore each regulation and control reaction 1 IKP number of increase, 2 regulation and control reactions here increase by 2 IKP numbers.Can
With regarding k7And k8For 2 IKP, such k-7And k-8Then become 2 RKPs (i.e. nuisance parameter).For the k of redundancy-7And k-8Arbitrarily
It is assigned a value of：k-7=C2, k-8=C3, thus we obtain k7And k8Value be：k7=C2Keq1, k8=C3Keq2.It is for example, artificial given
k-7≡C2=10-6, k-8≡C3=10-6, then 4 elementary reaction rate constants ks that regulation and control are reacted are related toiThus it is determined
For,
k7=10-6Keq1 (10-1)k-7=10-6 (10-2)k8=10-6Keq2 (10-3)k-8=10-6 (10-4)
The each independent reaction that can be solved by the above method and the elementary reaction speed constant of regulation and control reaction it is exhausted
After value and/or relative value, it is anti-primitive can be built with reference to elementary reaction topological dynamics equation and conservation of mass restriction relation
Answer topological structure type dynamic metabolism network.
The positive effect of the present invention is：The elementary reaction speed constant and its number of redundancy are determined in the method for the present invention
After mesh, this kind of special elementary reaction speed constant with assignment or can be set to fixed constant, and remaining elementary reaction speed is normal
Number can utilize the michaelis-Menton kinetics parameter that experiment measures, according to the pass of rice formula dynamics class parameter and elementary reaction speed constant
System obtains, and without deriving michaelis-Menton kinetics class rate equation analytic expression one by one, on the premise of having thermodynamic equilibrium constant, obtains
The involved elementary reaction speed constant of regulation and control reaction is fairly simple, is suitable for computer and builds large-scale metabolism network.This method
Can be by the michaelis-Menton kinetics parameter that experiment in vitro measures, or the information using existing database, total calculation go out primitive
Reactive kinetics parameters, can not only accurate quantitative description metabolism network, and operated easy to computer automation so that
Large-scale in silico metabolism networks must be built using elementary reaction to be possibly realized.
Embodiment
Embodiment 1
Enzyme reaction：The phosphofructose of 6 glucose 1-phosphate1-s → 6, enzyme are glucose phosphate isomerase, molecular weight M=12000Da.
The reaction is single substrate mono-product species irreversible reaction, and elementary reaction formula is as follows,
Wherein S represents 6 glucose 1-phosphate1-s, and E represents glucose phosphate isomerase, and P represents 6 phosphofructoses, and EP represents that enzyme is answered
Compound, k1、k2And k3For elementary reaction speed constant.
Under quasi-stable state hypothesis, elementary reaction kinetics equation is：
And the classical Michaelis-Menten equation of substrate mono-product species reaction is：
Wherein michaelis-Menton kinetics parameter includes Michaelis constant KmWith catalytic constant kcat。
k1、k2、k3And Km、kcatThere are following correlation,
And Michaelis constant K can be obtained by experimentmWith catalytic constant kcat, it is specially：
Michaelis-Menten equation is taken double reciprocal：
Take different concentration of substrate [S]1, [S]2..., [S]n, can measure to obtain reaction rate v1, v2..., and vn, withIt is rightMap to obtain a straight line, its straight line and transverse axis interceptSo as to obtain Km；With vertical axis interceptSo as to obtain
Vmax.For the pure enzymes of 0.08g, 25 DEG C, K is measured under the conditions of pH=7m=60.25mM, Vmax=10.60mMs-1, kcat=1590s-1。
Further combined withUnderstand：
k2=kcat=1590s-1, and k1And k-1In to have one be nuisance parameter, optional one such as k1Join as redundancy
Number, then k during solution1It can be considered constant, can then try to achieve k-1=Km*k1-k2, k can be given according to definition1Assign arbitrarily on the occasion of, into
And k can be tried to achieve-1.As a result, any k for meeting above-mentioned two restriction relation1And k-1(it should be more than according to known to definition
Zero), i.e. dynamic resolution, can all cause the speed of the enzyme reaction that identical change occurs.And utilize above-mentioned 3 elementary reaction speed normal
The reaction rate of number characterization is identical with the reaction rate represented completely with actual value.
It can be seen that the k of above-mentioned gained2, and k1And k-1Dynamic resolution can be used for characterize enzyme reaction：The phosphorus of 6 glucose 1-phosphate1-s → 6
Tart fruit sugar.With same method, same type or other different types of reactions also solve and obtain that corresponding reaction can be characterized one by one
Dynamic resolution, these dynamic resolutions can be used for structure dynamic metabolism network, and whole process without deriving michaelis-Menton kinetics class speed one by one
Rate equation analytic expression.And on the premise of having thermodynamic equilibrium constant, obtain the involved elementary reaction speed of regulation and control reaction
Constant is fairly simple, is suitable for computer and builds large-scale metabolism network.
Claims (3)
- A kind of 1. method that dynamic metabolism network is built according to elementary reaction topological structure, it is characterised in that comprise the following steps：(a) for the dynamic metabolism network to be built, all isolated reactions and regulation and control reaction and the Michaelis power being related to are found out Parameter and elementary reaction speed constant are learned, determines the independent power number of parameters of each isolated reaction and regulation and control reaction, into And determine the elementary reaction speed constant number of redundancy in each isolated reaction；Wherein, each isolated reaction and regulation and control are anti- The elementary reaction speed constant number of redundancy is respectively elementary reaction speed constant sum and the independent power that it is related in answering The difference of number of parameters；(b) Michaelis for measuring by experiment in vitro or obtaining all isolated reactions from existing zymetology database and regulating and controlling reaction moves Mechanics parameter；(c) in each isolated reaction, using the michaelis-Menton kinetics parameter of step (b) acquisition, to the elementary reaction speed of redundancy Constant assignment is set to fixed constant, with reference to the relation between michaelis-Menton kinetics parameter and elementary reaction speed constant, calculates Go out the absolute value or relative value of remaining all elementary reaction speed constant that isolated reaction is related to；(d) in each regulation and control reaction, using the michaelis-Menton kinetics parameter of step (b) acquisition, to the elementary reaction speed of redundancy Constant assignment is set to fixed constant, with reference to the relation between michaelis-Menton kinetics parameter and elementary reaction speed constant, calculates Go out the relative value of remaining all elementary reaction speed constant that regulation and control reaction is related to；(e) the elementary reaction speed constant obtained using step (c) and (d), elementary reaction topological structure is built by computer Type dynamic metabolism network.
- 2. the method as described in claim 1, it is characterised in that determine that each isolated reaction and regulation and control are reacted in step (a) Independent power number of parameters concretely comprise the following steps：First according to respectively with michaelis-Menton kinetics parameter and elementary reaction speed constant Have for the michaelis-Menton kinetics rate equation analytic expression of two kinds of forms of parameter, and michaelis-Menton kinetics rate equation analytic expression The restrictive condition of solution is limited, the independent power parameter number in each isolated reaction and regulation and control reaction is determined by mathematical simulation Mesh.
- 3. the method as described in claim 1, it is characterised in that in step (e), elementary reaction topological structure type dynamic metabolism net Network includes the elementary reaction rate equation and enzyme amount constraints of the compound of each metabolin and enzyme.
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| CN111341382A (en) * | 2020-02-20 | 2020-06-26 | 江南大学 | Macroscopic dynamics and cell metabolism flux coupling modeling method in lysine biological manufacturing |
| WO2022098470A1 (en) * | 2020-11-09 | 2022-05-12 | X Development Llc | In silico enzymology |
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