Macrophage Migration Inhibitory Factor (MIF): A Critical Upstream Regulator of Acute and Chronic Inflammatory Responses

Rice, Glenn C.; Liittschwager, Kurt; Metz, Christine N.; Bucala, Richard

doi:10.1016/s0065-7743(08)61089-1

Annual Reports in Medicinal Chemistry

1998

DOI: 10.1016/s0065-7743(08)61089-1

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Macrophage Migration Inhibitory Factor (MIF): A Critical Upstream Regulator of Acute and Chronic Inflammatory Responses

Glenn C. Rice

Kurt Liittschwager

Christine N. Metz³

et al.

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Cited by 2 publications

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“…Recently, it was discovered that PPT is the same protein as a mammalian cytokine known as macrophage migration inhibitory factor (MIF) (5). MIF has been implicated in various immune and inflammatory processes and in the development of sepsis (6)(7)(8)(9), adult respiratory distress syndrome (10), rheumatoid arthritis (11), and glomerulonephritis (11). Thus, it became of interest to determine whether there is a connection between the PPT activity and any of the biological activities of MIF, as PPT inhibitors might assist in the development of novel antiinflammatory agents (12)(13)(14)(15).…”

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confidence: 99%

Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants^,

et al. 2000

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Phenylpyruvate tautomerase (PPT) has been studied periodically since its activity was first described over forty years ago. In the last two years, the mechanism of PPT has been investigated more extensively because of the discovery that PPT is the same protein as the immunoregulatory cytokine known as macrophage migration inhibitory factor (MIF). The mechanism of PPT is likely to involve general base-general acid catalysis. While several lines of evidence implicate Pro-1 as the general base, the identity of the general acid remains unknown. Crystal structures of MIF with the competitive inhibitor (E)-2-fluoro-p-hydroxycinnamate bound in the active site and that of the protein complexed with the enol form of a substrate, (p-hydroxyphenyl)pyruvate, suggest that Tyr-95 is the only candidate in the vicinity that can function as a general acid catalyst. Although Tyr-95 is nearby the bound inhibitor and substrate, it is not within hydrogen bonding distance of either ligand. In this study, Tyr-95 was mutated to phenylalanine, and the kinetic and structural properties of the Y95F mutant were determined. This alteration produces a fully active enzyme, which shows no significant structural changes in the active site. The results indicate that Tyr-95 does not function as the general acid catalyst in the reaction catalyzed by wild-type PPT. The mechanism of PPT was studied further by constructing and characterizing the kinetic properties of two mutants of Pro-1 (P1G and P1A) and one mutant of Asn-97 (N97A). The mutation of Asn-97, a residue implicated in the binding of the phenolic hydroxy group of the keto and enol isomers of (p-hydroxyphenyl)pyruvate and of (E)-2-fluoro-p-hydroxycinnamate affects only the binding affinity of the inhibitor. However, the mutations of Pro-1 have a profound effect on the values of k(cat) and k(cat)/K(m) and clearly show that Pro-1 is a critical residue in the reaction. The results are discussed in terms of a mechanism in which Pro-1 functions as both the general acid and the general base catalyst.

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Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants^,

et al. 2000

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“…Macrophage migration inhibitory factor (MIF) 1 was among the first cytokine activities identified and has since been implicated in a variety of immune and inflammatory processes (1)(2)(3)(4). Because MIF plays a role in sepsis (5), and may be involved in the pathogenesis of adult respiratory distress syndrome (6), rheumatoid arthritis (7), and glomerulonephritis (7), it is a potential therapeutic target. One possible avenue for the design of such therapeutics makes use of the observation that MIF exhibits an enzymatic activity (8).…”

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confidence: 99%

A Kinetic and Stereochemical Investigation of the Role of Lysine-32 in the Phenylpyruvate Tautomerase Activity Catalyzed by Macrophage Migration Inhibitory Factor

et al. 1999

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Macrophage migration inhibitory factor (MIF), an immunoregulatory protein, exhibits a phenylpyruvate tautomerase (PPT) activity. The catalytic mechanism of this activity has recently attracted attention in an effort to determine whether there is a relationship between the PPT activity and the role of MIF in various immune and inflammatory processes. One of the active site residues is lysine-32, which is postulated to play two roles: it assists in substrate binding through an interaction with a carboxylate oxygen at C-1 of phenylpyruvate, and it may be partially responsible for lowering the pK(a) of the catalytic base, Pro-1. The role of Lys-32 has been investigated by changing it to an alanine and an arginine and determining the kinetic parameters, the stereoselectivity, the competitive inhibition, and the pH dependence of the resulting K32A- and K32R-catalyzed reactions. For the K32R mutant, these properties are mostly comparable to those determined for the wild type with two exceptions. There is a modest decrease in the stereoselectivity of the reaction and in the binding affinity of the competitive inhibitor, (E)-2-fluoro-p-hydroxycinnamate. These differences are likely due to the increased steric bulk of arginine. For the K32A mutant, there are 11- and 12-fold decreases in k(cat) and k(cat)/K(m), respectively, using phenylenolpyruvate. Part of the decrease in activity can be attributed to the observed increase of 1. 3 units in the pK(a) of Pro-1. It was also found that the loss of the electrostatic interaction did not significantly affect the stereoselectivity of the K32A-catalyzed reaction, although it did result in a decrease in the binding affinity of the competitive inhibitor. The combination of these results indicates that the primary function of Lys-32 in the PPT activity of MIF is to lower the pK(a) of Pro-1. The interactions responsible for the stereoselectivity of the PPT activity were further delineated by examining the wild type- and K32A-catalyzed reactions with an alternate substrate, 2-hydroxy-2,4-pentadienoate, in which the phenyl group of phenylenolpyruvate is replaced with a double bond. The effect of this substitution is moderate as evidenced by the observation that the ketonization of 2-hydroxy-2,4-pentadienoate by the wild type protein is more stereoselective than the K32R-catalyzed ketonization of phenylenolpyruvate but not as stereoselective as the K32A-catalyzed ketonization of phenylenolpyruvate. However, the low degree of stereoselectivity observed for the K32A-catalyzed reaction indicates that an electrostatic interaction between the protein and 2-hydroxy-2, 4-pentadienoate is now crucial.

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Macrophage Migration Inhibitory Factor (MIF): A Critical Upstream Regulator of Acute and Chronic Inflammatory Responses

Cited by 2 publications

References 48 publications

Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants^,

Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants^,

A Kinetic and Stereochemical Investigation of the Role of Lysine-32 in the Phenylpyruvate Tautomerase Activity Catalyzed by Macrophage Migration Inhibitory Factor

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Macrophage Migration Inhibitory Factor (MIF): A Critical Upstream Regulator of Acute and Chronic Inflammatory Responses

Cited by 2 publications

References 48 publications

Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants,

Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants,

A Kinetic and Stereochemical Investigation of the Role of Lysine-32 in the Phenylpyruvate Tautomerase Activity Catalyzed by Macrophage Migration Inhibitory Factor

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Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants^,

Mechanism of the Phenylpyruvate Tautomerase Activity of Macrophage Migration Inhibitory Factor: Properties of the P1G, P1A, Y95F, and N97A Mutants^,