The structural and molecular biology of type III galactosemia

Type III galactosemia is a genetic disease caused by mutations in the gene encoding UDP-galactose 4-epimerase. A variety of different point mutations located throughout the gene can be responsible. The main, disease-causing effects of these mutations appear to be a reduction in the catalytic rate constant (kcat) and an increase in the proteolytic sensitivity of the protein. Many of the mutations are distant from the active site of the enzyme and therefore must be assumed to affect the overall fold of the protein. Although the disease was previously classified into a severe, or generalized, form and an essentially benign, or peripheral, form this distinction has been blurred by recent work. Instead of two separate conditions it now appears that type III galactosemia is a continuum and that the symptoms will vary depending on the mutation(s) carried by the individual sufferer. This new way of looking at the disease has implications for the treatment and long term monitoring of patients.     

2'-Functionalized nucleic acids as structural tools in molecular biology

Modified oligonucleotides bearing 2'-reactive groups or 2'-conjugated molecules have found wide application as structural tools in molecular biology. Of principal interest has been the use of 2'-reactive oligonucleotides for cross-linking with biomolecules and of 2'-conjugated oligonucleotides in hybridization assays. In this review we compare a range of electrophilic, nucleophilic and photoreactive groups for cross-linking and conjugation studies.     

Comparative genomics and structural biology of the molecular innovations of eukaryotes

Eukaryotes encode numerous proteins that either have no detectable homologs in prokaryotes or have only distant homologs. These molecular innovations of eukaryotes may be classified into three categories: proteins and domains inherited from prokaryotic precursors without drastic changes in biochemical function, but often recruited for novel roles in eukaryotes; new superfamilies or distinct biochemical functions emerging within pre-existing protein folds; and domains with genuinely new folds, apparently 'invented' at the outset of eukaryotic evolution. Most new folds emerging in eukaryotes are either alpha-helical or stabilized by metal chelation. Comparative genomics analyses point to an early phase of rapid evolution, and dramatic changes between the origin of the eukaryotic cell and the advent of the last common ancestor of extant eukaryotes. Extensive duplication of numerous genes, with subsequent functional diversification, is a distinctive feature of this turbulent era. Evolutionary analysis of ancient eukaryotic proteins is generally compatible with a two-symbiont scenario for eukaryotic origin, involving an alpha-proteobacterium (the ancestor of the mitochondria) and an archaeon, as well as key contributions from their selfish elements.