S-(2-oxopentadecyl)-CoA, a nonhydrolyzable analog of myristoyl-CoA, is a potent inhibitor of myristoyl-CoA: protein N-myristoyltransferase

Paige, Lisa A.; Zheng, Guozhong; DeFrees, Shawn; Cassady, John M.; Geahlen, Robert L.

doi:10.1021/jm00128a001

Cited by 58 publications

(38 citation statements)

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“…The K, was essentially similar to the apparent K,,, of yeast N-myristoyltransferase (4 x M). This result is in agreement with the data recently obtained by Paige et al [40] for S-(2-oxopentadecyl)-CoA (Ki = 2.4 x lo-' M).…”

Section: Inhibition Of Myristoylation By S-supporting

confidence: 93%

“…The first of them, myristoylcarba(dethia)-CoA is similar to heptadecan-2-onyldethiaCoA, a compound shown to be a competitive inhibitor for palmitoyltransferase (Ki = 3.3 x M) [25]. The second, S-(3-oxohexadecyl)-CoA is similar to S(2-oxopentadecy1)-CoA, also shown to be a non-hydrolysable inhibitor of mouse brain N-myristoyltransferase (Ki = 2.4 x lo-' M) [40]. However, the synthesis of S-(3-oxohexadecyl)-CoA is simpler and its purification procedure rapid and very effective.…”

Section: Inhibition Of Myristoylation By S-mentioning

confidence: 98%

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Synthesis of myristoyl‐carba(dethia)‐coenzyme A and S‐(3‐oxohexadecyl)‐coenzyme A, two potent inhibitors of myristoyl‐CoA: protein N‐myristoyltransferase

Wagner

Rétey

1991

European Journal of Biochemistry

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1. Two non-hydrolysable analogues of myristoyl-coenzyme A were synthesised and spectroscopically characterized. Myristoyl-carba(dethk)coenzyme A was prepared in a multistep synthesis starting from tridecyl vinyl ketone. S-(3-Oxohexadecyl)-coenzyme A was synthesised from 3-oxohexadecyl chloride by direct condensation with coenzyme A. In many cases, myristoylation of viral proteins is required for their association with the plasma membrane and for morphological transformation of cells [13 -151. It has also emerged that the myristoylation of retroviral gag proteins is essential for the assembly and maturation of virus particles Therefore it was of interest to determine whether nonhydrolysable fatty acyl-CoA analogues might prove to be effective inhibitors of myristoyl-CoA : protein N-myristoyltransferase which catalyses the co-translational linkage of myristoyl groups to the N-terminal glycine residues of several viral and cellular proteins.[16-181. MATERIALS AND METHODS MaterialsAcidic alumina and myristoyl chloride were from Merck (Darmstadt, FRG). ['4C]Myristoyl-CoA (54 Ci/mol) and [9,10(n)-3H]myristic acid (54 Ci/mmol, n indicates nominal position of labelling) were purchased from Amersham Buchler (Braunschweig, FRG). The octapeptide Gly-Asn-Ala-AlaCorrespondence to J. RCtey,

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Section: Inhibition Of Myristoylation By S-supporting

confidence: 93%

Section: Inhibition Of Myristoylation By S-mentioning

confidence: 98%

Synthesis of myristoyl‐carba(dethia)‐coenzyme A and S‐(3‐oxohexadecyl)‐coenzyme A, two potent inhibitors of myristoyl‐CoA: protein N‐myristoyltransferase

Wagner

Rétey

1991

European Journal of Biochemistry

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“…3B). Furthermore, 2-hydroxymyristate, a known inhibitor of myristoylation (41,42), inhibits membrane localization of Fyn and Fyn (16)-eGFP to a greater extent than 2-bromopalmitate (Fig. 2B).…”

Section: -Bromopalmitate Inhibits Fyn Fatty Acylation In Cos-1mentioning

confidence: 97%

Inhibition of Protein Palmitoylation, Raft Localization, and T Cell Signaling by 2-Bromopalmitate and Polyunsaturated Fatty Acids

Webb¹,

Hermida-Matsumoto

Resh

2000

Journal of Biological Chemistry

426

366

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The ability of the Src family kinases Fyn and Lck to participate in signaling through the T cell receptor is critically dependent on their dual fatty acylation with myristate and palmitate. Here we identify a palmitate analog, 2-bromopalmitate, that effectively blocks Fyn fatty acylation in general and palmitoylation in particular. Treatment of COS-1 cells with 2-bromopalmitate blocked myristoylation and palmitoylation of Fyn and inhibited membrane binding and localization of Fyn to detergent-resistant membranes (DRMs). In Jurkat T cells, 2-bromopalmitate blocked localization of the endogenous palmitoylated proteins Fyn, Lck, and LAT to DRMs. This resulted in impaired signaling through the T cell receptor as evidenced by reductions in tyrosine phosphorylation, calcium release, and activation of mitogen-activated protein kinase. We also examined the ability of long chain polyunsaturated fatty acids (PUFAs) to inhibit protein fatty acylation. PUFAs have been reported to inhibit T cell signaling by excluding Src family kinases from DRMs. Here we show that the PUFAs arachidonic acid and eicosapentaenoic acid inhibit Fyn palmitoylation and consequently block Fyn localization to DRMs. We propose that inhibition of protein palmitoylation represents a novel mechanism by which PUFAs exert their immunosuppressive effects.

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“…The x-ray structure of C. albicans apo-Nmt has been determined to 2.45-Å resolution (48), as have the structures of an S. cerevisiae Nmt1p⅐myristoyl-CoA binary complex (2.2 Å (45)) and two ternary complexes: Nmt1p⅐S-(2-oxo)pentadecylCoA⅐SC-58272 (2.9 Å (49)) and Nmt1p⅐S-(2-oxo)pentadecylCoA⅐GLYASKLA (2.5 Å (45)). S-(2-oxo)pentadecyl-CoA is a nonhydrolyzable myristoyl-CoA analog with a methylene group interposed between the reactive thioester carbonyl and sulfur (30). It is a potent competitive inhibitor of S. cerevisiae Nmt1p (K i ϭ 5 nM) that binds to the apo-enzyme with a similar thermodynamic signature as myristoyl-CoA (44).…”

Section: Reaction Mechanism Of Nmtmentioning

confidence: 99%

The Biology and Enzymology of ProteinN-Myristoylation

Farazi¹,

Waksman²,

Gordon³

2001

Journal of Biological Chemistry

505

491

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S-(2-oxopentadecyl)-CoA, a nonhydrolyzable analog of myristoyl-CoA, is a potent inhibitor of myristoyl-CoA: protein N-myristoyltransferase

Cited by 58 publications

References 0 publications

Synthesis of myristoyl‐carba(dethia)‐coenzyme A and S‐(3‐oxohexadecyl)‐coenzyme A, two potent inhibitors of myristoyl‐CoA: protein N‐myristoyltransferase

Synthesis of myristoyl‐carba(dethia)‐coenzyme A and S‐(3‐oxohexadecyl)‐coenzyme A, two potent inhibitors of myristoyl‐CoA: protein N‐myristoyltransferase

Inhibition of Protein Palmitoylation, Raft Localization, and T Cell Signaling by 2-Bromopalmitate and Polyunsaturated Fatty Acids

The Biology and Enzymology of ProteinN-Myristoylation

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