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Biomedical subjects

María Luz Cárdenas

Publications and source records attributed to María Luz Cárdenas.

7 recordsLinked to original sources
PubMed2005

Organizational invariance and metabolic closure: analysis in terms of (M,R) systems.

This article analyses the work of Robert Rosen on an interpretation of metabolic networks that he called (M,R) systems. His main contribution was an attempt to prove that metabolic closure (or metabolic circularity) could be explained in purely formal terms, but his work remains very obscure and we try to clarify his line of thought. In particular, we clarify the algebraic formulation of (M,R) systems in terms of mappings and sets of mappings, which is grounded in the metaphor of metabolism as a mathematical mapping. We define Rosen's central result as the mathematical expression in which metabolism appears as a mapping f that is the solution to a fixed-point functional equation. Crucially, our analysis reveals the nature of the mapping, and shows that to have a solution the set of admissible functions representing a metabolism must be drastically smaller than Rosen's own analysis suggested that it needed to be. For the first time, we provide a mathematical example of an (M,R) system with organizational invariance, and we analyse a minimal (three-step) autocatalytic set in the context of (M,R) systems. In addition, by extending Rosen's construction, we show how one might generate self-referential objects f with the remarkable property f(f)=f, where f acts in turn as function, argument and result. We conclude that Rosen's insight, although not yet in an easily workable form, represents a valuable tool for understanding metabolic networks.

Animals↗
PubMed2005

Abnormal kinetic behavior of uroporphyrinogen decarboxylase obtained from rats with hexachlorobenzene-induced porphyria.

Uroporphyrinogen decarboxylase is an essential enzyme in all organisms and functions in the heme biosynthetic pathway, catalyzing the decarboxylation of the four acetate groups of uroporphyrinogen to form coproporphyrinogen. This work examines whether the four sequential decarboxylations occur at the same active site, and explores whether hexachlorobenzene-induced porphyria affects the behavior of the enzyme. For this purpose, kinetic competition studies were done with mixtures of uroporphyrinogen III and pentacarboxyporphyrinogen III. With the enzyme from normal rats, a constant velocity was obtained with all the mixtures, indicating that uroporphyrinogen and pentacarboxy-porphyrinogen react at the same active site, i.e. the first and fourth decarboxylations occur at the same site. In contrast, in experiments with enzyme from rats with hexachlorobenzene-induced porphyria, the total rate for mixtures was always lower than the reference rate; and a curve with a deep minimum was obtained, indicating that the two reactions occur at functionally different sites, but with cross-inhibition. This suggests that the modifications induced in the enzyme by hexachlorobenzene cause the two active sites to become nonequivalent and functionally different. The question is discussed how the hexachlorobenzene treatment may produce this abnormal kinetic behavior, and alternative hypotheses are considered.

Animals↗
PubMed2004

Understanding the parts in terms of the whole.

Metabolism is usually treated as a set of chemical reactions catalysed by separate enzymes. However, various complications, such as transport of molecules across membranes, physical association of different enzymes, giving the possibility of metabolite channelling, need to be taken into account. More generally, a proper understanding of the nature of life will require metabolism to be treated as a complete system, and not just as a collection of components. Certain properties of metabolic systems, such as feedback inhibition of the first committed step of a pathway, make sense only if one takes a broader view of a pathway than is usual in textbooks, so that one can appreciate ideas such as regulation of biosynthesis according to demand. More generally still, consideration of metabolism as a whole puts the emphasis on certain systemic aspects that are crucial but which can pass unnoticed if attention is always focussed on details. For example, a living organism, unlike any machine known or conceivable at present, makes and maintains itself and all of its components. Any serious investigation of how this can be possible implies an infinite regress in which each set of enzymes needed for the metabolic activity of the organism implies the existence of another set of enzymes to maintain them, which, in turn, implies another set, and so on indefinitely. Avoiding this implication of infinite regress represents a major challenge for future investigation.

Animals↗
PubMed2003

Kinetic studies of rat liver hexokinase D ('glucokinase') in non-co-operative conditions show an ordered mechanism with MgADP as the last product to be released.

The kinetic mechanism of rat liver hexokinase D ('glucokinase') was studied under non-co-operative conditions with 2-deoxyglucose as substrate, chosen to avoid uncertainties derived from the co-operativity observed with the physiological substrate, glucose. The enzyme shows hyperbolic kinetics with respect to both 2-deoxyglucose and MgATP(2-), and the reaction follows a ternary-complex mechanism with K (m)=19.2+/-2.3 mM for 2-deoxyglucose and 0.56+/-0.05 mM for MgATP(2-). Product inhibition by MgADP(-) was mixed with respect to MgATP(2-) and was largely competitive with respect to 2-deoxyglucose, suggesting an ordered mechanism with 2-deoxyglucose as first substrate and MgADP(-) as last product. Dead-end inhibition by N -acetylglucosamine, AMP and the inert complex CrATP [the complex of ATP with chromium in the 3+ oxidation state, i.e. Cr(III)-ATP], studied with respect to both substrates, also supports an ordered mechanism with 2-deoxyglucose as first substrate. AMP appears to bind both to the free enzyme and to the E*dGlc complex. Experiments involving protection against inactivation by 5,5'-dithiobis-(2-nitrobenzoic acid) support the existence of the E*MgADP(-) and E*AMP complexes suggested by the kinetic studies. MgADP(-), AMP, 2-deoxyglucose, glucose and mannose were strong protectors, supporting the existence of binary complexes with the enzyme. Glucose 6-phosphate failed to protect, even at concentrations as high as 100 mM, and MgATP(2-) protected only slightly (12%). The inactivation results support the postulated ordered mechanism with 2-deoxyglucose as first substrate and MgADP(-) as last product. In addition, the straight-line dependence observed when the reciprocal value of the inactivation constant was plotted against the sugar-ligand concentration supports the view that there is just one sugar-binding site in hexokinase D.

Acetylglucosamine↗
PubMed2003

Metabolic analysis in drug design.

Biotechnology is often presented as if progress in the past two decades represented a major success, but the reality is quite different. For example, ten major classes of antibiotics were discovered between 1935 and 1963, but after 1963 there has been just one, the oxazolidones. To illustrate the possibilities of doing better by taking account of the real behaviour of metabolic systems, we can examine how one might modify the activity of an enzyme in the cell (for example by genetic manipulation, or by the action of an inhibitor, etc.) to satisfy a technological aim. For example, if the objective is to eliminate a pest, one might suppose that the effect of an inhibitor could be to depress an essential flux to a level insufficient for life, or to raise the concentration of an intermediate to a toxic level. The former may seem the more obvious, but the latter is easier to achieve in practice, and there are some excellent examples of industrial products that work in that way, such as the herbicide 'Roundup' and antimalarials of the quinine class. A study of glycolysis in the parasite Trypanosoma brucei (which causes African sleeping sickness) indicates that for this approach to work the selected target enzyme must have a substrate with a concentration that is not limited by stoichiometric constraints. That is not necessarily easy to find in a complicated system, and typically needs the metabolic network to be analysed in the computer.

Animals↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗