Cofactors primitive 203

The above description provides a possible starting background for the description of the beginning of cellular chemotypes, prokaryotes, but even this is less complicated than the only cells for which we have evidence since they have at least two additional groups of more sophisticated chemicals - coenzymes (see Tables 5.3 and 5.4) and certain metal cofactors, which we presume were additions to the most primitive cells. After we have described them, we shall return to the problem of cellular (cytoplasmic) organisation. Note that coenzyme novelty is not in basic pathways but in control of rates and in energy management. 

The above account of selectivity of inorganic plus organic chemistry in synthesis is given rather extensively to stress three points. All the four (Mg, Fe, Co and Ni) porphyrin products came from one source, the synthesis of uroporphyrin. The basis of selection is very different from that in primitive centres which use thermodynamic stability constant selectivity based on different donor atoms for different metal ions. Here, all ion complexes have the same donor atoms, nitrogen, the most constrained being the coordination of Mg2+ by five nitrogens exactly as is seen for Fe in haemoglobin. Hence, there also has to be a new control feedback to ensure that the appropriate quantities of each metal cofactor is produced in a balanced way, that is synthesis from uroporphyrin has to be divided based upon... 

The search for RNAs with new catalytic functions has been aided by the development of a method that rapidly searches pools of random polymers of RNA and extracts those with particular activities SELEX is nothing less than accelerated evolution in a test tube (Box 26-3). It has been used to generate RNA molecules that bind to amino acids, organic dyes, nucleotides, cyano-cobalamin, and other molecules. Researchers have isolated ribozymes that catalyze ester and amide bond formation, Sn2 reactions, metallation of (addition of metal ions to) porphyrins, and carbon-carbon bond formation. The evolution of enzymatic cofactors with nucleotide handles that facilitate their binding to ribozymes might have further expanded the repertoire of chemical processes available to primitive metabolic systems. 

What the mechanistic baseline provided by a model reaction does do is to suggest where molecular evolution may have necessarily started, although it must be remembered that substrates and enzymes have co-evolved so that the chemical scope of a primitive substrate may not be that of a modem substrate. Furthermore, a model-reaction mechanism may indicate what processes it was necessary for an enzyme to avoid in order to open the way for a comparatively unfavorable reaction to be catalyzed. One of the most striking examples is provided by the recent studies of Kluger and his coworkers of the unexpected chemical properties of the cofactor thiamin diphosphate [25-29]. Although this work has nothing explicitly to do with... 

PLP itself, however, is presumably much older than this. There are general arguments suggesting that organic cofactors and coenzymes represent biochemical fossils from very primitive stages in the history of life. In particular, the fact that several cofactors show nucleotide-like features is often used to support the occurrence of an RNA world, that is, a very early phase of biotic evolution in which RNA molecules were capable of self-replication and of a rudimentary form of metabolism. Within this hypothetical world, cofactors and coenzymes would have helped expand the chemical repertoire of catalytic RNAs. "... 

The general arguments about the antiquity of cofactors apply to PLP. The nonenzymatic synthesis of pyridoxal under prebiotic conditions is considered possible, whereas the presence of a 5 phosphate group could hint to an ancestral attachment of the cofactor to RNA molecules. " Furthermore, there are specific grounds to assume that PLP arrived on the evolutionary scene before the emergence of proteins. In fact, in current metabolism, PLP-dependent enzymes play a central role in the synthesis and interconversion of amino acids, and thus they are closely related to protein biosynthesis. In an early phase of biotic evolution, free PLP could have played many of the roles now fulfilled by PLP-dependent enzymes, since the cofactor by itself can catalyze (albeit at a low rate) reactions such as amino acid transaminations, racemizations, decarboxylations, and eliminations. " This suggests that the appearance of PLP may have preceded (and somehow eased) the transition from primitive RNA-based life forms to more modern organisms dependent on proteins. 

The nickel-containing factor F 430 (134) provides an example of how nature exploits the reactivity of organometallic compounds, as is the case with vitamin B12. Factor F 430 (134) plays a key role as cofactor for the coenzyme M reductase of primitive methanogenic bacteria in the formation of methane from 2-(methylthio)-ethanesulfonate (86). The structural elucidation of factor F 430 (134) is based on a combination of classical spectroscopic methods, chemical degradation, and biosynthetic studies with C-labelled precursors 83a,b). These biosynthetic investigations will be addressed in section 8.2. Chemical degradation products obtained by ozonolysis of factor F 430 (134) allowed the determination of the absolute configuration by comparison with reference compounds derived from chlorophyll a (2) and vitamin B12 (4) 83a,b). 

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