Application of phosphonate and thiophosphate analogues of nucleotides to studies of some enzyme reactions

Abstract

The enzymatic cleavage of a scissile P-0 The opportunities for the application of phosphonate analogues of biological phosphate esters are as many and varied as the enzymes that operate on phosphate esters. Their successful application in agriculture and in medicine leaves no doubt about the scientific and industrial importance of these species. Thus, glyphosate (1) is arguably the world's most successful herbicide, with sales in excess of 1 x lo9$ per annum, a range of substituted methylene bisphosphonates, e.g. hydroxyethylidenebisphosphonate (2), are important for the control of osteoporosis and related problems, phosphonomycin (3) is a useful broad-spectrum antibiotic, while phosphonoacetic acid (4) remains the standard test compound for evaluation of inhibitors of the HIV reverse transcriptase (Scheme 1). Rational analysis shows that phosphonate analogues of phosphate monoesters (5a) can either replace one of the nonbridging oxygens, as in a meth-0 1991 VCH Publishers, Inc.

Regiospecificity of the hydrolysis of diadenosine polyphosphates catalyzed by three specific pyrophosphohydrolases

“…In our studies, we have confirmed these observations and, moreover, shown that the AP4A homologue, ApsA, is cleaved with incorporation of 180 only into ADP [for the FAB MS profile, see Blackburn et al (1991)]. These data show that the enzyme accepts the nucleoside tetraphosphate moiety in the substrate and directs water, as second substrate, at P4.…”

Recent progress in the study of the intracellular functions of diadenosine polyphosphates

“…It has to be noted that the introduction of each P(S) moiety creates a new stereochemical center in the nucleotide analog, for which chirality can be controlled either by stereospecific synthesis or by chromatographic separation of diastereoisomers. Some early results showed a preference for one or the other chirality at the P(S) center for resistance to specific enzyme cleavage, while good overall affinity for the protein was retained [Blackburn et al, 1990a].…”

The Synthesis of Dialkyl α-Halogenated Methylphosphonates

“…[1][2][3][4] Unlike phosphates, the phosphonate linkage is not susceptible to hydrolysis by esterases and is chemically stable. Phosphonates play an important and useful role in our lives from the many and varied biological applications such as antiviral agents (acyclic nucleoside phosphonates), [5][6][7] as inhibitors of gene expression in mammalian cells (oligonucleoside methylphosphonates) 8 and as antibiotics 4,9,10 (phosphonomycin 11 ). They have become important in the treatment of bone-disorder (Clodronate 12 , Etidronate 13 ) and in medical decalcification (e.g.…”