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A12. The Role of Fe/S Centers

Let's return to the chicken and egg dilemma one more time.  What is needed for biological polymer formation are monomeric precursors, an energy source, and a way to compartmentalized them all.  We discuss how monomeric precursors could form, but wouldn't it be far better if even the synthesis of precursors could be catalyzed?  One source of catalysis mostly absent from  the "bioorganic" abiotic chemistry in the above discussion is the transition metals.  Transition metals can form complexes.  Ligands containing lone pairs on O, N, and S atoms can donate them to transition metals ions, which can hold up to 18 electrons in s, p, and d orbitals.  Hence as many as 9 lone pairs on ligand molecules (which are often multidentate) could be accommodated around the transition metal ion. Many present small molecule metabolites and their abiotic precursors (H2O, CO, CO2, NH3 and thiols) bind cations as mono- or polydentate donors of electrons.  Hence transition metal ions would have a thermodynamic tendencies to be bound in complexes.  

Bound ligands that contain potentially ionizable hydrogens could become deprotonated and made better nucleophiles for reactions.  Hence the transition state metal ion, acting with the complex, becomes a catalyst as it decreases the pKa of a bound ligand (such as water). In addition, since transition metals ions can have multiple charge and oxidation states, they can easily act as redox centers in the oxidation/reduction of bound ligands that were redox active.  Given the relative anoxic conditions of the early oceans, Fe2+ would predominant.  It could easily be oxidized  to Fe3+ as it reduced a bound ligand.  Highly charged transition states would withdraw electron density from bound ligands leading to their possible oxidation. 

Metals obviously still play a strong role in catalysis, both indirectly in promoting correct protein folding and directly in stabilizing charge in both the transition state and intermediates in chemical reaction pathways.  FeS clusters are of significant importance.  Their biosynthesis involves removal by an active site Cys in a desulfurase enzyme of a sulfur from a free amino acid Cys followed by its transfer to an Fe in a growing FeS cluster in a FeS scaffold protein, which then transfers the cluster to an acceptor protein where it acts as a cofactor. FeS clusters can adopt a variety of stoichiometries and shapes, as well as redox states for the participating Fe ions. The continuing importance of FeS clusters in all cells, their involvement in not only redox enzymes in which electron transfer is facilitated by delocalization of electrons over both Fe and S centers, but also in coupled electron/proton transport in mitochondrial electron transport, Fe storage (ferrodoxins),  and in regulation of enzyme activity and gene expression, suggests that they were of primordial importance in the evolution of life.    

They are often found at substrate binding sites of FeS enzymes involved in both redox and nonredox catalysis.  A ligand can bind to a particular Fe in the cluster, activating it for hydration or dehydrogenation reactions.  Fe 4 of the FeS cluster in the TCA enzyme aconitase can have a coordination numbers of 4, 5, or 6 as it binds water, hydroxide or substrate.  It acts to both decrease electron density in the transition state and to change the pKa of bound water as the enzyme catalyzes an isomerization of tricarboxylic acids (citric and isocitric acid) through an elimination/addition reaction with water.  In another example it can bind S-adenosylmethionine through its amine and carboxylate groups, which activates the molecule for cleavage and radical formation.  In some cases metals other than Fe (Ni for example) are incorporated into the cluster. FeS effects on transcription factors involves facilitation of optimal structure for DNA binding.  FeS and FeNi centers in proteins are similar in structure tp FeS units in minerals like greigite and presumably to FeS structure formed when H2S and S2- react with Fe2+ (present in abundance in the early ocean) and other metals in vents   Metal sulfides participate in reduction of both CO and CO2.  For example the synthesis of CH3SH from CO2 and H2S is catalyzed by "inorganic" FeS.

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