Synthetic Models for Hemoglobin and Myoglobin

Abstract

1) Myoglobin and Hemoglobin. Dioxygen (O 2 ) binds to certain coordinatively unsaturated transition metal ions, forming O 2 complexes. Biological dioxygen carriers are reversible O 2 complexes in which the extent of binding depends on temperature, partial pressure of oxygen, and pH.Myoglobin (Mb) and hemoglobin (Hb) are the most common reversible O 2 binders in biological systems; they are responsible for the storage and transport of O 2 in most aerobic organisms. Myoglobin and hemoglobin are structurally similar. Myoglobin contains one heme prosthetic group; hemoglobin consists of four Mb-like subunits (2R + 2 ), each containing one heme prosthetic group.Myoglobin stores O 2 in muscles to permit short bursts of metabolism at rates much greater than those which would be allowed by circulatory oxygen transport. In its native deoxy form (Figure 1), the ferrous ion of the heme is in a five-coordinate high-spin state (S ) 2), with the imidazole group (His 93) serving as the axial ligand on the proximal side. Myoglobin reversibly binds molecular oxygen in the sixth, distal, vacant coordination site. Distal amino acid residues (e.g., His 64) control the immediate environment. They can induce polar, hydrophobic, or steric interactions which help regulate the affinities of the bound ligands.Hemoglobin, on the other hand, transports O 2 in blood and adjusts binding affinity to various conditions required for appropriate uptake and release of O 2 through a series of allosteric interactions. 1,2 Through the "allosteric effect", the subsequent gas binding affinity of Hb is made greater in the presence of O 2 or carbon monoxide (CO) than in their absence. Myoglobin, having only one heme site per protein, shows no such effect.(2) Control of Ligand-Binding Thermodynamics. Evidence to date suggests that the amino acid residues on the distal porphyrin face are capable of stabilizing the oxygen adduct while destabilizing the competing complex derived from binding of the endogenous toxic ligand CO. 3 Studies have shown that, in the absence of the globin protein, imidazole-ligated heme has a CO affinity much greater than that of the protein-bound heme, indicating that the protein plays a role in decreasing CO affinity. 4 The most significant distal effect invoked in the stabilization of O 2 in Hb is the hydrogen-bonding interaction between coordinated O 2 and the distal histidine, which was initially proposed by Pauling. 5 Subsequent experiments have provided evidence for H-bonding of ironbound dioxygen with the distal histidine. 6-10 A unique Hb from the bloodworm Ascaris (shown in Figure 2) has a remarkably high affinity for O 2 , nearly 10 4 times that of mammalian Hb. 11,12 The origin of this high O 2 affinity is believed to be (1) a strong H-bond between tyrosine (Tyr

Fe L-Edge X-ray Absorption Spectroscopy of Low-Spin Heme Relative to Non-heme Fe Complexes: Delocalization of Fe d-Electrons into the Porphyrin Ligand

“…cytochromes a, b, c and f) [1][2][3] which cycle between low-spin Fe(II) and low-spin Fe(III), small molecule binding and transport, 4,5 catalysis and O 2 activation (e.g. peroxidases and cytochromes P450) [6][7][8][9][10][11] where high valent Fe centers are involved in H atom abstraction, hydroxylation and epoxide formation.…”

“…15,16 In contrast, there has been significant controversy over the assignment of the electron distribution between the Fe and the O 2 in oxyhemoglobin. 4,[20][21][22][23][24][25][26][27][28] Spectroscopic methods that have been used to probe the electron distribution in the d-orbitals of ferro-and ferriheme systems include NMR, 29,30 EPR and Mössbauer. [31][32][33] In systems with a low spin Fe(III) center, EPR is able to probe the energy splitting of the d xy , d xz , d yz orbitals, 34,35 and can thus provide insight into the π donation of the heme center compared to that of axial ligands.…”

Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation

“…The R and T states of oxyhemoglobin can be replicated demonstrating the effect on equilibrium binding of O 2 as well as the role steric hindrance plays in that effect (6). The relative CO/O 2 binding in model hemes can be varied by a factor of Ͼ4000 by manipulating the distal pocket of models (7,8). Recently, a functional cytochrome c oxidase (CcO) model was created that reduces O 2 to H 2 O under conditions of biomimetic rate limiting electron flux (9).…”

Adjusting the binding thermodynamics, kinetics, and orientation of guests within large synthetic hydrophobic pockets

“…As alluded to above, we recently determined the thermodynamics of association for baskets 2a-c in three different solvents: CDCl 3 , toluene-d 8 , and DMSO-d 6 . We wished to determine how the presence of a methyl group or a hydroxyl group affected both the strength of association between the host and adamantane guests and the orientation of the guest within the host.…”

“…Two approaches are common. Either the enzymes themselves can be studied by means of mutagenesis (3) or they can be mimicked (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) by using small model compounds, which possess much of the functionality, or catalytic machinery, seen in the active site of the enzyme in question. With respect to the latter, a shift in emphasis toward considering the context of the catalytic machinery within the enzyme has recently become apparent.…”