Analogs of palmitoyl-CoA that are substrates for myristoyl-CoA:protein N-myristoyltransferase.

doi:10.1073/PNAS.89.21.10507

Paper

Analogs of palmitoyl-CoA that are substrates for myristoyl-CoA:protein N-myristoyltransferase.

Published Nov 1, 1992 · D. Rudnick, T. Lu, E. Jackson-Machelski

Proceedings of the National Academy of Sciences of the United States of America

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Abstract

Saccharomyces cerevisiae myristoyl-CoA:protein N-myristoyltransferase (Nmt1p; EC 2.3.1.97) is an essential enzyme that is highly selective for myristoyl-CoA in vivo. It is unclear why myristate (C14:0), a rare cellular fatty acid, has been selected for this covalent protein modification over more abundant fatty acids such as palmitate (C16:0), nor is it obvious how the enzyme's acyl-CoA binding site is able to discriminate between these two fatty acids. Introduction of a cis double bond between C5 and C6 of palmitate [(Z)-5-hexadecenoic acid] or a triple bond between C4 and C5 or C6 and C7 (Y4- and Y6-hexadecenoic acids) yields compounds that, when converted to their CoA derivatives, approach the activity of myristoyl-CoA as Nmt1p substrates in vitro. Kinetic studies of 42 C12-C18 fatty acids containing triple bonds, para-phenylene, or a 2,5-furyl group, as well as cis and trans double bonds, suggest that the geometry of the enzyme's acyl-CoA binding site requires that the acyl chain of active substrates assume a bent conformation in the vicinity of C5. Moreover, the distance between C1 and the bend appears to be a critical determinant for optimal positioning of the acyl-CoA in this binding site so that peptide substrates can subsequently bind in the sequential ordered bi-bi reaction mechanism. Identification of active, conformationally restricted analogs of palmitate offers an opportunity to "convert" wild-type or mutant Nmts to palmitoyltransferases so that they can deliver these C16 fatty acids to critical N-myristoylproteins in vivo. nmt181p contains a Gly-451-->Asp mutation, which causes a marked reduction in the enzyme's affinity for myristoyl-CoA. Strains of S. cerevisiae containing nmt1-181 exhibit temperature-sensitive myristic acid auxotrophy: their complete growth arrest at 37 degrees C is relieved when the medium is supplemented with 500 microM C14:0 but not with C16:0. The CoA derivatives of (Z)-5-hexadecenoic and Y6-hexadecynoic acids are as active substrates for the mutant enzyme as myristoyl-CoA at 24 degrees C. However, unlike C16:0, they produce growth arrest of nmt181p-producing cells at this "permissive" temperature, suggesting that these C16 fatty acids do not allow expression of the biological functions of essential S. cerevisiae N-myristoylproteins.

Study Snapshot

This study identifies active, conformationally restricted analogs of palmitate as substrates for myristoyl-CoA:protein N-myristoyltransferase, offering a potential method to "convert" wild-type or mutant Nmts to palmitoyltransferases

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Analogs of palmitoyl-CoA that are substrates for myristoyl-CoA:protein N-myristoyltransferase.

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References

Mutations of human myristoyl-CoA:protein N-myristoyltransferase cause temperature-sensitive myristic acid auxotrophy in Saccharomyces cerevisiae.

Human myristoyl-CoA:protein N-myristoyltransferase (NMT) is 44% identical to yeast NMT, and its mutations cause temperature-sensitive myristic acid auxotrophy in Saccharomyces cerevisiae, indicating highly conserved structure-function relationships

A multisubunit particle implicated in membrane fusion

NSF, SNAPs, and an integral membrane component form a multisubunit protein complex that can disassemble and reassemble, potentially enhancing specificity in NSF-dependent fusion apparatus.

The Candida albicans myristoyl-CoA:protein N-myristoyltransferase gene. Isolation and expression in Saccharomyces cerevisiae and Escherichia coli.

Candida albicans and Saccharomyces cerevisiae NMTs have similar substrate specificities, but distinct kinetic properties, which may have therapeutic significance.

Substrate specificity of Saccharomyces cerevisiae myristoyl-CoA: protein N-myristoyltransferase. Analysis of fatty acid analogs containing carbonyl groups, nitrogen heteroatoms, and nitrogen heterocycles in an in vitro enzyme assay and subsequent identification of inhibitors of human immunodeficienc

The enzyme myristoyl-CoA-protein N-myristoyltransferase (NMT) has a dipolar binding site and its activity decreases with increasing polarity, making it a potential target for antiviral and antifungal therapy.

N-myristoylation is required for function of the pheromone-responsive G alpha protein of yeast: conditional activation of the pheromone response by a temperature-sensitive N-myristoyl transferase.

N-myristoylation is essential for the function of the yeast pheromone-responsive G alpha protein, Gpa1, and other proteins essential for vegetative growth.

Citations

Dual Role of ACBD6 in the Acylation Remodeling of Lipids and Proteins

ACBD6 plays a dual role as a carrier and regulator of acyl-CoA dependent reactions, controlling lipid and protein composition in human cell membranes.

Mapping the myristoylome through a complete understanding of protein myristoylation biochemistry.

Protein myristoylation serves as a molecular anchor in living organisms, allowing targeted proteins to membranes and travel across endomembrane networks.

Protein Lipidation by Palmitoylation and Myristoylation in Cancer

Palmitoylation and myristoylation play crucial roles in modulating cancer metabolism, affecting cancer initiation and progression.

NMT as a glycine and lysine myristoyltransferase in cancer, immunity, and infections.

NMT, a glycine and lysine myristoyltransferase, plays a crucial role in cancer, immunity, and infections, with potential for targeted pharmacological targeting.

Requirement of the acyl-CoA carrier ACBD6 in myristoylation of proteins: Activation by ligand binding and protein interaction

ACBD6 plays a crucial role in protecting N-myristoyltransferase enzymes from unwanted acyl-CoA species and supports the N-myristoylation of proteins in human cells.