title en

Journal archive > 2007 > N 6 November-December


V. K. Kibirev, T. V. Osadchuk, Yu. L. Radavsky

Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv;
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The survey deals with structure, properties and biological role of furin, the calcium-dependent­ serine endoprotease, which is expressed in all tissues and cell lines examined. It is the best-charac­terized representative of the mammalian subtilisin-like family of proprotein convertases, which is capable to cleave precursors of a wide variety of proteins, including hormones, growth factors, serum proteins, proteases of the blood-clotting system, matrix metalloproteinases, receptors, viral envelope glycoproteins, and bacterial exotoxins, and so on. The enzyme plays the essential role in embryogenesis, homeostasis; it is also involved in tumor metastasis, activation and virulence of many bacterial and viral pathogens and in neurodegenerative processes associated with Alzheimer’s disease. Furin is a very specific enzyme: it recognizes the cleavage-site sequence Arg-Xaa-Lys/Arg-Arg? and catalyzes the hydrolysis of the precursors, containing a pair of basic amino acids Arg-Arg or Lys-Arg. The enzyme is a multidomain protein which is initially synthesized as 100 kDa glycosylated profurin consisting of 794 amino acid residues (for human furin) and including a N-terminal signal peptide, propeptide, catalytic domain, possessing ~ 30% homology to subtilisin, a well-conserved P-domain, Cys-rich domain, transmembrane domain and cytoplasmic domain. The active site cleft of furin differs considerably from that of subtilisin with respect to the depth, shape and molecule charge. In furin it is a canyon-like groove with clusters of negatively charged residues along it. Furin inhibitors are rather promising therapeutic agents for treating furin-mediated diseases and bacterial infections. Most furin inhibitors belong to proteins or peptides. The protein-based inhibitors include both naturally occurring and bioengineered variants of protease inhibitors. The peptide-based inhibitors are represented by polyarginines, peptidyl chloromethyl ketones, aminomethyl ketones or ketomethylene pseudopeptides, isostere-containing cyclic peptides, short peptides derived from the prosegments of furin or ?1-PDX-related peptides. The nonpeptide inhibitors are natural products of the andrographolide family, certain metal complexes of pyridine derivatives and small molecules derived from 2.5-dideoxystreptamine. The furin inhibitors may be used not only as valuable tools for studying furin action, but also as therapeutic agents for furin-dependent diseases.

Key words: furin, proprotein convertases, primary structure, domain arrangement, substrate specificity, substrates of furin, inhibitors of furin.

The original article in Russian is available for download in PDF format.

© The Ukrainian Biochemical Journal