S-adenosyl-L-methionine (AdoMet) dependent methyltransferases (MTases) are involved in biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing. Five different structural folds (I-V) have been described that bind AdoMet and catalyze methyltransfer to diverse substrates, although the great majority of known MTases have the Class I fold. Even within a particular MTase class the amino-acid sequence similarity can be as low as 10%. Thus, the structural and catalytic requirements for methyltransfer from AdoMet appear to be remarkably flexible.'There are many paths to the top of the mountain, but the view is always the same.'…Chinese proverb [(1996) The Columbia World of Quotations, New York Columbia University Press] Following ATP, S-adenosyl-L-methionine (AdoMet) is the second most widely used enzyme substrate [1]. The majority of AdoMet-dependent reactions involve methyltransfer, leaving the product S-adenosyl-L-homocysteine (AdoHcy). The huge preference for AdoMet over other methyl donors, such as folate, reflects favorable energetics resulting from the charged methylsulfonium center: the ΔG° for (AdoMet + Hcy → AdoHcy + Met) is −17 kcal mol −1 -over double that for (ATP → ADP + P i ) [1]. Methylation substrates range in size from arsenite to DNA and proteins, and the atomic targets can be carbon, oxygen, nitrogen, sulfur or even halides [2,3].The first structure of an AdoMet-dependent methyltransferase (MTase), determined in 1993, was for the DNA C5-cytosine MTase M.HhaI [4]. For several years thereafter, a variety of additional MTases, with a wide range of different substrates, were found to share the same basic structure. More recently however, AdoMet-dependent methylation has been found to be the target of functional convergence that is catalyzed by enzymes with remarkably distinct structures. The Protein Data Bank (PDB) currently includes >100 structures for 50 distinct AdoMet-dependent MTases from 31 different classes of enzymes as defined by the Enzyme Classification (EC) system (Table 1; for a more extensive list see Ref.[5]).The purpose of this review is to compare and contrast the five known structurally distinct families of AdoMet-dependent MTases (Classes I-V). The phenomenon of enzymes from distinct structural families catalyzing the same reaction, termed enzyme analogy, has been noted for several decades [6] pluripotency that can be shaped by mutation and selection [7,8]. This can lead to a given protein structure playing several distinct catalytic roles [9], but also results in distinct protein structures playing a common catalytic role. Perhaps such flexibility is particularly easy where highly exergonic reactions are involved. As ATP is the only enzyme substrate more widely used than AdoMet, it seems logical that the current champion for greatest number of analogous families is the ATP-dependent protein phosphoryltransferases (protein kinases), with seven known structurally distinct families [10]. Nonetheless, this degree of analogy appears to be quite ra...

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A nomenclature is described for restriction endonucleases, DNA methyltransferases, homing endonucleases and related genes and gene products. It provides explicit categories for the many different Type II enzymes now identified and provides a system for naming the putative genes found by sequence analysis of microbial genomes.

HIV entry inhibitors include coreceptor antagonists and the fusion inhibitor T-20. T-20 binds the first helical region (HR1) in the gp41subunit of the viral envelope (Env) protein and prevents conformational changes required for membrane fusion. HR1 appears to become accessible to T-20 after Env binds CD4, whereas coreceptor binding is thought to induce the final conformational changes that lead to membrane fusion. Thus, T-20 binds to a structural intermediate of the fusion process. Primary viruses exhibit considerable variability in T-20 sensitivity, and determinants outside of HR1 can affect sensitivity by unknown mechanisms. We studied chimeric Env proteins containing different V3 loop sequences and found that gp120͞coreceptor affinity correlated with T-20 and coreceptor antagonist sensitivity, with greater affinity resulting in increased resistance to both classes of entry inhibitors. Enhanced affinity resulted in more rapid fusion kinetics, reducing the time during which Env is sensitive to T-20. Reduced coreceptor expression levels also delayed fusion kinetics and enhanced virus sensitivity to T-20, whereas increased coreceptor levels had the opposite effect. A single amino acid change (K421D) in the bridging sheet region of the primary virus strain YU2 reduced affinity for CCR5 and increased T-20 sensitivity by about 30-fold. Thus, mutations in Env that affect receptor engagement and membrane fusion rates can alter entry inhibitor sensitivity. Because coreceptor expression levels are typically limiting in vivo, individuals who express lower coreceptor levels may respond more favorably to entry inhibitors such as T-20, whose effectiveness we show depends in part on fusion kinetics.