Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.1 (sulfatase)
 3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sulfamide moiety, similarly to the structurally related sulfonamide and sulfamate ones, is widely employed in medicinal chemistry for the design of biologically active compounds. Amongst the enzymes for which sulfamide-based inhibitors were designed are the carbonic anhydrases (CAs), and a large number of proteases belonging to the aspartic protease (HIV-1 protease, gamma-secretase), serine protease (elastase, chymase, tryptase and thrombin, among others) and metalloproteinase (carboxypeptidase A [CPA] and matrix metalloproteinase [MMP]) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays an important role in the binding of the inhibitor to the active site cavity. This is achieved either by directly coordinating to the metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or, as in the case of the cyclic sulfamides, acting as HIV protease inhibitors interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HN-SO(2)-NH motif that substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physicochemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability etc., due to the intrinsic properties of this highly polarised moiety when attached to an organic scaffold. This interesting motif is, thus, of great value for the design of pharmacological agents with many applications.
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PMID:The sulfamide motif in the design of enzyme inhibitors. 2014 8

Arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) is reduced in several malignancies, but levels in melanoma have not been investigated previously. Experiments were performed in melanoma cell lines to determine ARSB activity and impact on melanoma invasiveness. ARSB activity was reduced ~50% in melanoma cells compared to normal melanocytes. Silencing ARSB significantly increased the mRNA expression of chondroitin sulfate proteoglycan(CSPG)4 and pro-matrix metalloproteinase(MMP)-2, known mediators of melanoma progression. Also, invasiveness and MMP activity increased when ARSB was reduced, and recombinant ARSB inhibited invasiveness and MMP activity. Since the only known function of ARSB is to remove 4-sulfate groups from the N-acetylgalactosamine 4-sulfate residue at the non-reducing end of chondroitin 4-sulfate (C4S) or dermatan sulfate, experiments were performed to determine the transcriptional mechanisms by which expression of CSPG4 and MMP2 increased. Promoter activation of CSPG4 was mediated by reduced binding of galectin-3 to C4S when ARSB activity declined. In contrast, increased pro-MMP2 expression was mediated by increased binding of the non-receptor tyrosine phosphatase SHP2 to C4S. Increased phospho-ERK1,2 resulted from SHP2 inhibition. Combined effects of increased C4S, CSPG4, and MMP2 increased the invasiveness of the melanoma cells, and therapy with recombinant ARSB may inhibit melanoma progression.
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PMID:Decline in arylsulfatase B leads to increased invasiveness of melanoma cells. 2792 79