29:
pathway, to characterize a single factor or reaction (namely the slowest), which plays the role of a master or rate-limiting step. In other words, the study of flux control can be simplified to the study of a single enzyme since, by definition, there can only be one 'rate-limiting' step. Since its conception, the 'rate-limiting' step has played a significant role in suggesting how metabolic pathways are controlled. Unfortunately, the notion of a 'rate-limiting' step is erroneous, at least under steady-state conditions. Modern biochemistry textbooks have begun to play down the concept. For example, the seventh edition of
43:
state of reaction chains, the principle of the master reaction has no application". Hearon (1952) made a more general mathematical analysis and developed strict rules for the prediction of mastery in a linear sequence of enzyme-catalysed reactions. Webb (1963) was highly critical of the concept of the rate-limiting step and of its blind application to solving problems of regulation in metabolism. Waley (1964) made a simple but illuminating analysis of simple linear chains. He showed that provided the intermediate concentrations were low compared to the
473:
coefficient.’ This described the relative change of one variable to another for small perturbations. In his Ph.D. thesis, Higgins describes many properties of the reflection coefficients, and in later work, three groups, Savageau, Heinrich and
Rapoport and Jim Burns in his thesis (1971) and subsequent publications independently and simultaneously developed this work into what is now called
994:
Savageau, Michael A. (1972). "The
Behavior of Intact Biochemical Control Systems* *This will not be an exhaustive review of the different methods for analyzing biochemical systems, but rather a selective treatment of one particular approach. Reviews covering alternative approaches to these problems
28:
Blackman (1905) stated as an axiom: "when a process is conditioned as to its rapidity by a number of separate factors, the rate of the process is limited by the pace of the slowest factor." This implies that it should be possible, by studying the behavior of a complicated system such as a metabolic
42:
From the 1920s to the 1950s, there were a number of authors who discussed the concept of rate-limiting steps, also known as master reactions. Several authors have stated that the concept of the 'rate-limiting' step is incorrect. Burton (1936) was one of the first to point out that: "In the steady
24:
is a step that controls the rate of a series of biochemical reactions. The statement is, however, a misunderstanding of how a sequence of enzyme catalyzed reaction steps operate. Rather than a single step controlling the rate, it has been discovered that multiple steps control the rate. Moreover,
472:
The modern perspective is that rate-limitingness should be quantitative and that it is distributed through a pathway to varying degrees. This idea was first considered by
Higgins in the late 1950s as part of his PhD thesis where he introduced the quantitative measure he called the ‘reflection
33:
explicitly states: "It has now become clear that, in most pathways, the control of flux is distributed among several enzymes, and the extent to which each contributes to the control varies with metabolic circumstances". However, the concept is still incorrectly used in research articles.
188:
1182:
Burns, J.A.; Cornish-Bowden, A.; Groen, A.K.; Heinrich, R.; Kacser, H.; Porteous, J.W.; Rapoport, S.M.; Rapoport, T.A.; Stucki, J.W.; Tager, J.M.; Wanders, R.J.A.; Westerhoff, H.V. (1985). "Control analysis of metabolic systems".
323:
values of the enzymes. The first point to note from the above equation is that the pathway flux is a function of all the enzymes; there is no need for there to be a 'rate-limiting' step. If, however, all the terms
481:. These developments extended Higgins’ original ideas significantly, and the formalism is now the primary theoretical approach to describing deterministic, continuous models of biochemical networks.
77:
254:
70:
462:
427:
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357:
301:
651:
321:
274:
210:
1078:"A Linear Steady-State Treatment of Enzymatic Chains. Critique of the Crossover Theorem and a General Procedure to Identify Interaction Sites with an Effector"
951:
Savageau, Michael A. (February 1971). "Parameter
Sensitivity as a Criterion for Evaluating and Comparing the Performance of Biochemical Systems".
665:
Zuo, Jianlin; Tang, Jinshuo; Lu, Meng; Zhou, Zhongsheng; Li, Yang; Tian, Hao; Liu, Enbo; Gao, Baoying; Liu, Te; Shao, Pu (24 November 2021).
563:
536:
553:
484:
The variations in terminology between the different papers on metabolic control analysis were later harmonized by general agreement.
1016:
635:
183:{\displaystyle {\frac {1}{F}}={\frac {1}{Q}}\left({\frac {R}{e_{1}}}+\ldots {\frac {X}{e_{i}}}+\ldots +{\frac {Z}{e_{n}}}\right)}
464:
then the first enzyme will contribute the most to determining the flux and therefore, could be termed the 'rate-limiting' step.
1215:
503:
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478:
474:
1220:
215:
718:"The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment"
1037:"A Linear Steady-State Treatment of Enzymatic Chains. General Properties, Control and Effector Strength"
46:
667:"Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis"
976:
918:
767:
Burton, Alan C. (December 1936). "The basis of the principle of the master reaction in biology".
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Zhou, Daoying; Duan, Zhen; Li, Zhenyu; Ge, Fangfang; Wei, Ran; Kong, Lingsuo (14 December 2022).
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279:
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Kacser, H.; Burns, J. A.; Kacser, H.; Fell, D. A. (1 May 1995). "The control of flux".
1094:
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are functions of the rate constants and intermediate metabolite concentrations. The
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753:
702:
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879:
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Hearon, John Z. (1 October 1952). "Rate
Behavior of Metabolic Systems".
612:
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580:
861:
964:
893:
Higgins, Joseph (May 1963). "Analysis of
Sequential Reactions".
25:
each controlling step controls the rate to varying degrees.
72:
values of the enzymes, the following expression was valid:
1076:
Heinrich, Reinhart; Rapoport, Tom A. (February 1974).
1035:
Heinrich, Reinhart; Rapoport, Tom A. (February 1974).
435:
400:
365:
330:
309:
282:
262:
218:
198:
80:
49:
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Kacser, H; Burns, JA (1973). "The control of flux".
552:Rajvaidya, Neelima; Markandey, Dilip Kumar (2005).
456:
421:
386:
351:
315:
295:
268:
248:
204:
182:
64:
1122:Symposia of the Society for Experimental Biology
846:"A note on the kinetics of multi-enzyme systems"
477:or, in the specific form developed by Savageau,
938:Kinetic properties of sequential enzyme systems
769:Journal of Cellular and Comparative Physiology
833:. New York: Academic Press. pp. 380–382.
8:
1115:
1113:
303:terms are proportional to the limiting rate
895:Annals of the New York Academy of Sciences
650:: CS1 maint: location missing publisher (
626:Nelson, David L.; Cox, Michael M. (2017).
527:Nelson, David L.; Cox, Michael M. (2005).
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940:. University of Pennsylvania: PhD Thesis.
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995:have recently been presented (28, 33)".
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997:Current Topics in Cellular Regulation
249:{\displaystyle Q,R,\ldots ,X,\ldots }
7:
628:Lehninger Principles of biochemistry
529:Lehninger Principles of Biochemistry
31:Lehninger Principles of Biochemistry
1095:10.1111/j.1432-1033.1974.tb03319.x
1054:10.1111/j.1432-1033.1974.tb03318.x
1009:10.1016/B978-0-12-152806-5.50010-2
907:10.1111/j.1749-6632.1963.tb13382.x
630:(Seventh ed.). New York, NY.
597:10.1093/oxfordjournals.aob.a089000
56:
14:
1149:Biochemical Society Transactions
1082:European Journal of Biochemistry
1041:European Journal of Biochemistry
65:{\displaystyle K_{\mathrm {m} }}
831:Enzyme and metabolic inhibitors
558:. APH Publishing. p. 408.
1:
808:10.1152/physrev.1952.32.4.499
581:"Optima and Limiting Factors"
212:equals the pathway flux, and
1197:10.1016/0968-0004(85)90008-8
1237:
829:Webb, John Leyden (1963).
735:10.3389/fphar.2022.1091779
555:Environmental Biochemistry
531:. Macmillan. p. 195.
504:Biochemical systems theory
499:Metabolic control analysis
479:biochemical systems theory
475:metabolic control analysis
844:Waley, Sg (1 June 1964).
722:Frontiers in Pharmacology
684:10.3389/fimmu.2021.779787
936:Higgins, Joseph (1959).
579:Blackman, F. F. (1905).
429:, are small relative to
671:Frontiers in Immunology
457:{\displaystyle R/e_{1}}
422:{\displaystyle Z/e_{n}}
387:{\displaystyle S/e_{2}}
352:{\displaystyle X/e_{i}}
781:10.1002/jcp.1030090102
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38:Historical perspective
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296:{\displaystyle e_{i}}
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468:Modern perspective
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22:rate-limiting step
959:(5286): 542–544.
862:10.1042/bj0910514
565:978-81-7648-789-4
538:978-0-7167-4339-2
494:Branched pathways
316:{\displaystyle V}
269:{\displaystyle Z}
205:{\displaystyle F}
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1221:Enzyme kinetics
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591:(74): 281–295.
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509:Committed step
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1088:(1): 97–105.
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18:biochemistry
15:
775:(1): 1–14.
728:: 1091779.
1210:Categories
1128:: 65–104.
1003:: 63–130.
677:: 779787.
515:References
646:cite book
605:0305-7364
244:…
232:…
153:…
130:…
923:30821044
915:13954410
816:13003538
754:36588722
703:34899740
613:43235278
488:See also
1169:7672373
1134:4148886
1104:4830199
1063:4830198
981:4297185
973:4925348
880:5840711
871:1202985
745:9795015
694:8651870
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953:Nature
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192:where
977:S2CID
919:S2CID
609:JSTOR
359:from
1165:PMID
1130:PMID
1100:PMID
1059:PMID
1013:ISBN
969:PMID
911:PMID
876:PMID
812:PMID
750:PMID
699:PMID
652:link
632:ISBN
601:ISSN
560:ISBN
533:ISBN
256:and
20:, a
1193:doi
1157:doi
1090:doi
1049:doi
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961:doi
957:229
903:doi
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858:doi
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