N-( 3-Di hyd roc holesteryloxyca rbonyl methyl 141) and N-(3-choIesteryIoxycarbonyI methyl 1-1 -aza-4,7,10,13-tetraoxacyclopentadecane (2) aggregate in water to form the first examples of niosomes based on amphiphiles having an uncomplexed crown ether residue as the head group.
Saccharomycescerevasiae myristoyl-CoA:protein N-myristoyltransferase (Nmtlp; 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 ofa cis double bond between C5 and C6 of palmitate [(Z)-5-hexadecenoic acid] or a triple bond between C4 and CS or C6 and C7 (Y4-and Y6-hexadecynoic acids) yields compounds that, when converted to their CoA derivatives, approach the activity of myristoyl-CoA as Nmtlp substrates in vitro. Kinetic studies of 42 C12-C18 fatty acids containing triple bonds, paraphenylene, 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. nmtl81p contains a Gly-451 -* Asp mutation, which causes a marked reduction in the enzyme's affimty for myristoyl-CoA. Strains of S. cerevisiae containing nmtl-181 exhibit temperature-senstive myristic acid auxotrophy: their complete growth arrest at 37C is relieved when the medium is supplemented with 500 FM 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 24C. However, unlike C16:0, they produce growth arrest of nmtl8lp-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.
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