Inhibition of Zinc Metallopeptidases by Flavonoids and Related Phenolic Compounds: Structure-Activity Relationships

Abstract

Flavonoids and other benzopyrone substances, having an appropriate hydroxylation profile, may inhibit the metalloenzymes leucine aminopeptidase (LAP), aminopeptidase M (AP-M), and carboxypeptidase A (CP-A). A structural feature that evidently favours the interaction between flavonoids and the three metalloenzymes is the 2,3-double bond conjugating the A and B rings and conferring a planar structure. This can be considered virtually indispensable for inhibition of the three metallopeptidases, though the hydroxylation profile required differed for each of the enzymes, and the interaction mechanism and behaviour also differed. The inhibitory effect of flavonoids on LAP was reversible, and to be effective the flavonoid had to have conjugated A and B rings and ortho-dihydroxylation on at least one of the aromatic rings. This same requirement was essential for inhibition by coumarins and was attributed to a catechol-like mechanism of interaction. The inhibitory effects on AP-M were due to inactivation of the enzyme, irreversibly altered by flavonoids with a 2,3-double bond and a minimum of one hydroxyl substituent on each of the aromatic rings. With CP-A, conjugation of the A and B rings enhanced the inhibitory effect of flavonoids, though it was not strictly required. The interaction between the polyphenolic substances tested and the two zinc aminopeptidases was not reversed by adding zinc to the reaction medium, indicating that the inhibition is not due to the coordination of the phenolic hydroxyl groups with the catalytical zinc of active site, though the presence of zinc affected the interaction behaviour differently according to each substance's hydroxylation profile.

Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa

“…The inhibition of ACE by anthocyanins 1 and 2, may be probably due to the rigid planar structure of the molecule and the presence of ortho-dihydroxylation on the aromatic ring (Parellada and Suarez, 1998), besides appropriate hydroxylation, also a planar structure is indispensable for the metallopeptidases inhibition. Anthocyanins are the major constituents in Hibiscus sabdariffa (Kong et al, 2003) and are used as food colouring agents (Esselen and Sammy, 1975), and diverse pharmacological investigations have demonstrated their antioxidant activity, protective effects against induced hepatic toxicity in rats, DNA damage and peroxidase activity in human's blood (Ali et al, 2005).…”

Isolation and identification of bound compounds from corn bran and their antioxidant and angiotensin I-converting enzyme inhibitory activities

“…Quantitative structure activity relationship (QSAR) analysis showed that the number of hydroxyl groups on the benzene ring played a crucial role for activity of phenolic compounds and that substitution of hydroxyl groups by methoxy groups decreased activity [48]. This might because that hydroxyl groups in a phenolic compound could come into being complexes with metal ions, which are an active center of ACE [49,50]. Therefore, the metal ions of ACE were reduced and ACE activity decreased.…”

Structural and Functional Analysis of the Complex between Citrate and the Zinc Peptidase Carboxypeptidase A

“…M14 peptidases such as CPA and CPB, synthesized in the pancreas and secreted into the gastrointestinal tract, are the major zinc-dependent enzymes responsible for the release of the C-terminal amino acid residue from food protein [2]. Carboxypeptidase activity in the gastrointestinal tract may be modulated by dietary zinc [3, 4] or can be inhibited by some organic food components [5–7]. Also, changes in the genomic expression levels may control carboxypeptidase enzyme activity in digestion [8].…”