JTW's Evolutionary Origins - Author: Wood, John T.

Coenzyme and Enzyme Evolution

Enzymes help to accelerate the conversion of specific substrates to the corresponding products and may be divided into two classes:

• Simple enzymes.
• Conjugated enzymes.

Interestingly enough, simple enzymes may have been preceeded by the more complex conjugated enzymes.

Simple enzymes catalyze a chemical reaction by exploiting the chemical reactivities of the side chains within the twenty naturally occurring amino acids that make up the protein.

For conjugated enzymes to properly function, the presence of a coenzyme or cofactor is required.

For these enzymes, it is the coenzyme that provides the major catalytic component of the enzyme.

The bulk of the protein serves as a scaffolding that holds the substates and modulates the reaction center dynamics via amino acid side chain interactions with the cofactor/coenzyme.

Cofactors are relatively small, low molecular weight (MW ~600 g/mol), nonprotein, organic molecules and/or metallalic ions that enzymes bind and orient to carry out catalytic functions.

Examples of metal ions would Zn²⁺ (the cofactor for carbonic anhydrase), Cu²⁺, Mn²⁺, K⁺, and Na⁺.

Wachtershauser places great importance on the multipurpose and ubiquitous iron-sulfur clusters that serve as cofactors in many key enzymes of the metabolic core.

Conjugated enzymes are able to recognize the cofactor surface and bind them to evolutionarily conserved clefts deep within their catalytic centers.

The protein portion of these conjugated enzymes are referred to as apoenzymes, and the protein itself is catalytically inactive in the absence of the cofactor.

The apoenzyme is required not only to hold the cofactor in place, but also generally holds the substrate in the proper orientation to assist the formation of transition states.

The apoenzyme with the cofactor is referred to as the holoenzyme.

• Oxidoreductases catalyze oxidation-reduction reactions.
• Transferases catalyze transfer of functional groups from one molecule to another.
• Hydrolases catalyze hydrolytic cleavage.
• Lyases catalyze removal of a group from or addition of a group to a double bond, or other cleavages involving electron rearrangement.
• Isomerases catalyze intramolecular rearrangement.
• Ligases catalyze reactions in which two molecules are joined.

"The fact that so many coenzymes are nucleotides or heterocyclic bases that could be part of nucleotides intrigued me as did the fact that more than half of all characterized enzymes require these coenzymes to catalyze the essential chemistry.

In fact, when metal ions are considered, relatively few enzymes are exclusively protein catalysts.

It seemed to me that proteins were an epiphenomenon butilt around a preexisting catalytic core made of nucleotides." (White, 2002)

H.B. White (1976) proposed what has been called the "Principle of Many Users" which notes that "it is extremely unlikely for a structure that serves as a cofactor in many reactions to change while maintaining efficiency and specificity" (Lahav, 1999).

Noam Lahav notes: "this requirement is reflected in deep cofactor-binding clefts found in modern protein enzymes. With such specific recognition elements, cofactors are not likely to change easily" (Lahav, 1999).

It is this fact that Wachtershauser exploits in his quest for a preenzymatic catalyst.

Wachtershauser identifies iron-sulfur clusters as providing important clues as to the nature of the primordial reaction system.

Many ,but not all, coenzymes (ATP, CoenzymeA, NAD⁺, NADP⁺...) are related to nucleotides that contain nitrogenous heterocyclic purine rings.

These coenzymes were suggested by H.B. White to be "vestiges of nucleic acid enzymes which preceeded the evolution of the ribosomal protein synthesis".

These biocatalytic coenzyme "vestiges" date back almost 4 billion years, providing clues to the nature of the primordial autocatalytic reaction system.

Coenzymes, Wachtershauser considers to be vitalysts (Wachtershauser, 199_), chemical structures that catalyze there own formation as well as improving the robustness of the original metabolic core, the RCC and its extended feedback loops.

Upon the emergence of proteins, concerted amino acid moiety based catalysis emerged, with the new catalytic functions and structures becoming grafted onto the original metabolic core.

(It may well be that amino acids themselves also served as vitalysts within the primodial metabolic core.)

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