Metal cofactor interactions

Another aspect of electrostatic modulation of redox systems is metal cofactor interactions. Although these interactions are surprisingly uncommon in biological systems, metal-cofactor interactions have been well documented in certain families of enzymes such as bacterial alcohol dehydrogenases. These enzymes utilize the pyrroloquinolinequinone (PQQ) system as a redox cofactor (Figure 12) [45]. In these systems, it has been established that Ca + serves as additional cofactors in the enzymatic processes catalyzed by PQQ-dependent proteins [46]. 

The heme moiety provides de novo designed heme proteins with an intrinsic and spectroscopically rich probe. The interaction of the amide bonds of the peptide or protein with the heme macrocycle provides for an induced circular dichroism spectrum indicative of protein-cofactor interactions. The strong optical properties of the heme macrocycle also make it suitable for resonance Raman spectroscopy. Aside from the heme macrocycle, the encapsulated metal ion itself provides a spectroscopic probe into its electronic structure via EPR spectroscopy and electrochemistry. These spectroscopic and electrochemical tools provide a strong quantitative base for the detailed evaluation of the relative successes of de novo heme proteins. 

Enzyme Inhibition/Activation. A major site of toxic action for metals is interaction with enzymes, resulting in either enzyme inhibition or activation. Two mechanisms are of particular importance inhibition may occur as a result of interaction between the metal and sulfhydryl (SH) groups on the enzyme, or the metal may displace an essential metal cofactor of the enzyme. For example, lead may displace zinc in the zinc-dependent enzyme 5-aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme-containing enzymes, such as cytochromes. 

This is an auspicious time to publish a volume on copper proteins. The number of known proteins with metallic cofactors continues to increase steadily, and the availability of structural and sequence data is enabling much more specihc characterizations of the interactions between the metal ions and proteins as well as of their functions and mechanisms. Numerous investigators are choosing copper proteins and copper metabolism as their model systems for such studies. While copper-containing proteins play essential roles, their numbers are few enough that a comprehensive understanding is a reasonable goal. 

Non-covalent insertion of several modified metal cofactors and synthetic metal complexes into protein cavities such as serum albumin (SA) and Mb has been reported [5, 24, 28, 30, 69], If synthetic metal complexes, whose structures are very different from native cofactors, can be introduced into protein cages, the bioconjugation of metal complexes will be applicable to many proteins and metal complexes. Mn(corrole) and Cn(phthalocyanine) are inserted into SA by non-covalent interactions and the composites catalyze asymmetric sulfoxidation and Diels-Alder reactions with up to 74 and 98% ee, respectively (Fig. 2c) [28, 30], Since the heme is coordinated to Tyrl61 in the albumin cavity, determined by X-ray crystal structure [20], it is expected that both Mn(corrole) and Cu(phtalocyanine) are also bound to albumin with the same coordination. The incorporation of synthetic metal complexes in protein cavities using these methods is a powerful approach for asymmetric catalytic reactions. However, there are still some difficulties in further design of the composites for improving reactivities and understanding reaction mechanisms because detailed structural analyses are not available for most of the composites. 

Enzymes Toxicity of metals may arise from their actions on enzymes. Many metals may inhibit enzymes by (1) interacting with the SH group of the enzyme (2) displacing an essential metal cofactor of the enzyme, and (3) inhibiting the synthesis of enzyme. 

The impact of NO complexation by metal ions is of a crucial meaning to biological systems. NO reacts with all transition metals to give metal nitrosyls. Proteins containing transition metals are particularly prone to react with NO, since its unpaired electrrMi can interact and bond with the d-orbitals of metal cofactors. These interactions are widely used by the nature and function in various cellular regulatory pathways. It is clear that the diversity of the NO-sensing proteins... 

Metal ions, effect of size, 200-205 Metalloenzymes, see also Enzyme cofactors classification of, by cofactor and coupled general base, 205-207, 206 electrostatic interactions in, 205-207 SNase, 189-197... 

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