Fatty acyl transfer by human N-myristyl transferase is dependent upon conserved cysteine and histidine residues.

Peseckis, Steven M.; Resh, Marilyn D.

doi:10.1016/s0021-9258(18)47364-4

Cited by 45 publications

(13 citation statements)

References 23 publications

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“…If these compounds were acting at His-218, allowing the formation of an acylenzyme intermediate but not allowing the subsequent transfer to the peptide substrate, one would expect loss of radioactivity with hydroxylamine. Four histidine residues are highly conserved in human, yeast, bovine, nematode, and drosophila NMTs (17)(18)(19)(34)(35)(36)(37). Our studies, along with the existing knowledge, implicate the crucial role of histidine residues in the enzyme activity (18,20,21,33).…”

Section: Resultsmentioning

confidence: 54%

“…expect retention of radiolabel on NMT as acyl-enzyme intermediate. Such intermediates have been reported previously in human and yeast NMTs (15,18). Thus, the assay method cannot distinguish between radiolabel retained by the NMT (as an acyl-enzyme intermediate) or that bound to the peptide product.…”

Section: Resultsmentioning

confidence: 73%

“…The acyl-peptide generated in the enzyme assay is a competitive inhibitor for fatty acyl-CoA and a noncompetitive inhibitor for peptide (33), suggesting that the acyl-peptide can bind to the enzyme at its fatty acyl-CoA binding site but not at its peptide-binding site (15,33). Previously, it has been shown that mutation of His-293 interfered with the formation of acyl-enzyme intermediate while mutation of His-218 attenuated the generation of the myristoylated product (18). We wished to determine whether the inhibition of NMT activity by L-histidinol and histamine are interfering at His-293 or His-218.…”

Section: Resultsmentioning

confidence: 98%

“…Comparisons of four yeast, human, and bovine NMT sequences reveal conserved cysteine residues at amino acids 169 and 214 in hNMT and bovine spleen NMT (sNMT) (172 and 217 in Nmt1p) (17)(18)(19). In addition, 4 histidine residues are conserved [His-131, His-171, His-217, and His-293 in hNMT and sNMT; His-134, His-174, His-221, and His-296 in Nmt1p (17)(18)(19)]. It has been shown that fatty acid transfer by hNMT is dependent upon conserved cysteine and histidine residues (18).…”

mentioning

confidence: 99%

“…In addition, 4 histidine residues are conserved [His-131, His-171, His-217, and His-293 in hNMT and sNMT; His-134, His-174, His-221, and His-296 in Nmt1p (17)(18)(19)]. It has been shown that fatty acid transfer by hNMT is dependent upon conserved cysteine and histidine residues (18).…”

mentioning

confidence: 99%

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Effects of l-Histidine and Its Structural Analogues on Human N-Myristoyltransferase Activity and Importance of EEVEH Amino Acid Sequence for Enzyme Activity

et al. 1998

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Myristoyl-CoA:protein N-myristoyltransferase (NMT) is an essential eukaryotic enzyme that catalyzes the cotranslational transfer of myristate to the NH2-terminal glycine residue of a number of important proteins of diverse function. Human NMT (hNMT) activity was found to be activated by L-histidine in a concentration-dependent manner. In contrast, two structural analogues of L-histidine, L-histidinol and histamine, inhibited hNMT activity in a noncompetitive manner with half-maximal inhibitions of 18 and 1.5 mM, respectively. The inhibition of hNMT activity by L-histidinol was reversed by a 2-fold molar excess of L-histidine, suggesting that L-histidine and L-histidinol were competing for a common site on NMT. Kinetic data indicated that whereas L-histidine enhanced the Vmax, both L-histidinol and histamine decreased the Vmax; none of these compounds altered the Km. Our studies suggest that L-histidine and its analogues may be interacting with His-293, involved in myristoyl-CoA transfer, rather than His-218, and implicated in the transfer of myristoyl-CoA to the peptide substrates. Site-directed mutagenesis of His-293, Val-291, and Glu-290 resulted in proteins with no measurable NMT activity. The most conserved region in the catalytic domain EEVEH (289-293) is critical for the myristoyl-CoA transfer in the NMT-catalyzed reactions. This region will be useful for the design of regulators of NMT function.

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Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of l-Histidine and Its Structural Analogues on Human N-Myristoyltransferase Activity and Importance of EEVEH Amino Acid Sequence for Enzyme Activity

et al. 1998

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Selective peptidic and peptidomimetic inhibitors of Candida albicans myristoylCoA: Protein N-myristoyltransferase: A new approach to antifungal therapy

et al. 1997

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N‐Myristoyltransferase: a Prospective Drug Target for Protozoan Parasites

et al. 2008

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Parasite specific: The inhibition of myristoyl‐CoA:protein N‐myristoyltransferase (NMT) can lead to parasite death in culture. Herein we review recent work that supports the suitability of NMT as a parasite‐specific drug target. The example shown illustrates the peptidomimetic compound 2, which is more stable, yet retains the Ser and Lys functional groups of compound 1 that are necessary for NMT inhibition.

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Fatty acyl transfer by human N-myristyl transferase is dependent upon conserved cysteine and histidine residues.

Cited by 45 publications

References 23 publications

Effects of l-Histidine and Its Structural Analogues on Human N-Myristoyltransferase Activity and Importance of EEVEH Amino Acid Sequence for Enzyme Activity

Effects of l-Histidine and Its Structural Analogues on Human N-Myristoyltransferase Activity and Importance of EEVEH Amino Acid Sequence for Enzyme Activity

Selective peptidic and peptidomimetic inhibitors of Candida albicans myristoylCoA: Protein N-myristoyltransferase: A new approach to antifungal therapy

N‐Myristoyltransferase: a Prospective Drug Target for Protozoan Parasites

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