Microbial l-methioninase: production, molecular characterization, and therapeutic applications

Abstract

L-methioninase is ubiquitous in all organisms except in mammals. It mainly catalyzes the, alpha, gamma-elimination of L: -methionine to alpha-ketobutyrate, methanethiol, and ammonia. Unlike normal cells, methionine dependency was reported as a biochemical phenomenon among various types of cancer cells. Thus, L-methioninase is the universal protocol for triggering the majority of tumor cells. This review is an attempt to briefly describe the occurrence of the biochemical and molecular properties of L-methioninase by a comparative manner to the eukaryotic and prokaryotic source for the maximum exploitation in the therapeutic field. The combination of L-methioninase treatment, gene therapy, and chemotherapeutic drugs clearly explores the various therapeutic aspects of this enzyme. Finally, the perspectives for increasing the therapeutic efficacy of this enzyme were described.

Pre-steady-state Kinetic and Structural Analysis of Interaction of Methionine γ-Lyase from Citrobacter freundii with Inhibitors

“…The absorbance at 500 nm during interaction MGL with L-alanine and L-norvaline is slightly changed (data not shown) indicating that the quinonoid is a temporary intermediate and is not accumulated in the reaction. The simplest mechanism that can account for the kinetic data is presented in Scheme 4, and it includes the conversion of internal aldimine, absorbing at 420 nm, into complex (E⅐L-AA) 1 , which absorbs at 320 nm, and slow conversion of this complex into the external aldimine (E⅐L-AA) 2 , which absorbs at 420 nm. The calculated rate constants of the formation of the (E⅐L-AA) 2 complex in the reactions with L-alanine and L-norvaline are much less than the rate constants of the isotopic exchange of C␣-and C␤-protons in the both amino acids (Table 2).…”

“…The steady-state rate constant (k ex ) of the isotopic exchange of the two enantiotopic protons of glycine (35) are also presented in Table 2. Having compared the exchange rates with the other rates in Table 2, it was supposed that the complex (E⅐Gly) 1 , which absorbs at 420 nm and is formed in a millisecond time interval, probably corresponds to the external aldimine intermediate with orthogonal orientation of the "right" pro-R-proton (H r ) to the cofactor plane (Fig. 2, IIIa).…”

“…2, IIIb) in the reaction with glycine, responsible for the exchange of the wrong pro-S-proton. Thus, the isotopic exchange of both C␣-and C␤-protons of L-alanine and L-norvaline should proceed through the intermediate complex (E⅐L-AA) 1 , absorbing at 320 nm. For the exchange of ␤-protons, the formation of ketimine is strongly required (17), and we can reasonably suppose that the complex (E⅐L-AA) 1 corresponds to the ketimine, existing in a fast equilibrium with the enolimine tautomer of the external aldimine also absorbing at 320 nm.…”

“…In the case of L-cycloserine, the formation of (E⅐L-cycloserine) 1 complex reflects the formation of the external aldimine. The subsequent transformations (abstraction of C␣-proton and protonation of C4Ј atom of PLP) lead to accumulation of stable ketimine intermediate.…”

“…Methionine ␥-lyase (EC 4.4.1.11, MGL), 3 a pyridoxal 5Ј-phosphate (PLP)-dependent enzyme, is found in many bacteria (1), including the Enterobacteriaceae family (Citrobacter freundii (2)) and in pathogenic bacteria (Bacteroides sp. (3), Aeromonas sp.…”