Simple Heme Protein Models

The information provided adds to the evidence that it is not only heme proteins that are involved in oxygen sensing in various subcellular and cellular compartments but also intracellular free iron featured prominently in the process in the carotid body chemoreception. In doing so, molecules that activated HIF-a also activated 

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This work was supported in part by grants R37-HL43413-12, R01-HL50180-7, T32-HL07027-27, and US Navy NOOO14-01-1-0948. The secretarial assistance of Mary Pili is gratefliUy acknowledged. 

Lahiri S, DeLaney RG. Stimulus interaction in the response of carotid chemoreceptor single afferent fibers. Respir Physiol 1975 24 249-266. 

Lahiri A, Iturriaga R, Mokashi A, Ray DK, Chugh D. CO reveals dual mechanisms of O2 chemoreception in the cat carotid body. Respir Physiol 1993 94 227-240. 

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For monomeric host porphyrin framework, we may start from natural porphyrins such as protoporphyrin IX and its derivatives. In earlier times, the 3- and 8-vinyl and 13- and 17-propionates of protoporphyrin IX were subjected to simple chemical mc ifications like reduction, addition and condensation. The first chemical modification for synthesis of heme protein models reported by Lautch et al. is condensation of an oligopeptide with the two propionates. In order to mimic the proximity of the heme, terminal His or Cys of oligopeptide linked to the 13- and 17-propionates of heme can coordinate to the heme iron as axial ligands. 

The rich spectroscopy and electrochemistry of the heme moiety yields a wealth of opportunities for the denovo heme protein design to evaluate the success of the heme binding site design. Combinations of these spectroscopic and electrochemical methods are elucidating the structure and function of de novo heme proteins and illustrating that they serve as excellent bioinorganic model complexes for simple cytochromes. 

The analysis of redox potential modulation in heme proteins has been undertaken through both experimental and theoretical strategies. In particular, the use of simple models such as microperoxidase (MP) and the design of artificial heme proteins or biomimetics has allowed to single out the effect of different factors on redox potential [17, 18], There are a number of relevant interactions, listed on Table 4.2, related to the thermodynamics terms mentioned above and that have been shown to influence the redox potential of heme proteins and biomimetics. Although they may not entirely explain redox potential modulation, they are the best understood and several examples may be found in the literature. 

On the other hand, the simple complexes (hemins I and II) have a reverse relation between the ICD magnitudes in the Soret region and the ligand field strengths of the axial ligands bound to the heme for peptides and proteins. This difference between our models 199) and Urry s findings 196 198> may be partly due to the existence of the ring(s) with optically active center(s). 

The theory of the Fe(III) heme spectra has been given in the previous article (52) and in particular the difference between the absorption spectra of high-spin and low-spin species has been stressed. The application of this theory to some proteins has also been described in that article but its purpose was mainly to draw attention to normal spectra. Here we shall point to a number of anomalous spectra especially concerning the movement of the Soret band to much shorter wavelengths than 400 nm. There is a simultaneous notable broadening of this band and a fall in its extinction coefficient. Such effects have frequently been seen in simple model systems and so we deal these first. 

Cytochrome P-450, which is the most extensively studied of the monooxygenase proteins, has a heme-iron active center with an axial thiol ligand (a cysteine residue). However, most chemical model investigations use simple iron(III) porphyrins without thiolate ligands. As a result, model mechanisms for cytochrome P-450 invoke a reactive intermediate that is formulated to be equivalent to Compound I of horseradish peroxidase, (por+-)Fe =0, with a high-potential porphyrin cation radical. Such a species would be reduced by thiolate, and therefore is an unreasonable formulation for the reactive center of cytochrome P-450. 

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