Membrane alanyl and glutamyl aminopeptidases (APN and APA, respectively) are established targets for the development of biomedical tools in human pathologies. APN overexpression correlates with the progression of tumours, including melanoma. Bacitracin, widely used as a topical antibiotic, inhibits subtilisin-like serine peptidases and disulfide isomerases. In the present contribution we demonstrate that bacitracin is a non-competitive α=1 and α<1 inhibitor of porcine kidney APN and APA, respectively with K i values in the micromolar range. To test a potential application of this result, we assayed the effect of bacitracin on murine melanoma MB16F10 cell line viability. We demonstrated the cell line expresses an APN-like activity inhibited by bacitracin and bestatin. Additionally, we identified a cytotoxic effect of bacitracin.Further experiments are required to understand in depth the mechanisms of action of bacitracin on melanoma cells. They will clarify the therapeutic potential of bacitracin for melanoma treatment.

Proteolytic enzymes, also known as peptidases, are critical in all living organisms. Peptidases control the cleavage, activation, turnover, and synthesis of proteins and regulate many biochemical and physiological processes. They are also involved in several pathophysiological processes. Among peptidases, aminopeptidases catalyze the cleavage of the N-terminal amino acids of proteins or peptide substrates. They are distributed in many phyla and play critical roles in physiology and pathophysiology. Many of them are metallopeptidases belonging to the M1 and M17 families, among others. Some, such as M1 aminopeptidases N and A, thyrotropin-releasing hormone-degrading ectoenzyme, and M17 leucyl aminopeptidase, are targets for the development of therapeutic agents for human diseases, including cancer, hypertension, central nervous system disorders, inflammation, immune system disorders, skin pathologies, and infectious diseases, such as malaria. The relevance of aminopeptidases has driven the search and identification of potent and selective inhibitors as major tools to control proteolysis with an impact in biochemistry, biotechnology, and biomedicine. The present contribution focuses on marine invertebrate biodiversity as an important and promising source of inhibitors of metalloaminopeptidases from M1 and M17 families, with foreseen biomedical applications in human diseases. The results reviewed in the present contribution support and encourage further studies with inhibitors isolated from marine invertebrates in different biomedical models associated with the activity of these families of exopeptidases.

Aminopeptidases selectively hydrolyze an aminoacid residue from the amino terminus of proteins and peptides resulting in their activation or inactivation. These enzymes are mainly metallo and belong, among other, to the M1 family of peptidases. One of its members, membrane glutamyl aminopeptidase (APA, EC 3.4.11.7) participates in many physiological processes, such as peptide metabolism related with blood pressure control, and last step of protein degradation. Furthermore, the up regulation of APA has been implicated in the pathogenesis of various human disorders like cancers, hypertension and glomerulosclerosis. APA is thus a target for the development of inhibitors with potential biomedical applications. We review the most important structural and functional characteristics of mammalian APA, focusing on the most recent data. Additionally, we integrate the roles of APA in physio- and pathophysio-logical processes of biomedical relevance with the development of specific APA inhibitors.