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Plant-Based Adjunct Therapy for Tuberculosis
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Lydia Gibango, Anna-Mari Reid, Jonathan L. Seaman, Namrita Lall
β-lactamase inhibitors are mainly used to overcome the resistance to β-lactam antibiotics. As previously mentioned, these adjuvants protect against the inactivation of the antibiotic by enzymes. Bacterial inactivation involves β-lactamases that hydrolyze the β-lactam core of β-lactams through a process based on acylation-deacylation (González-Bello, 2017). In the 1980s, the first β-lactamase inhibitor was used in combination with penicillin. Diazabicyclooctanes have been under investigation since the mid-1990s as β-lactam mimics, and later were found to be efficient β-lactamase inhibitors (Bush, 2018). Boronic acids are used as transition state analogs. The development of these compounds was discovered when serine proteases were inhibited by boronic acids (Smoum et al., 2012).
Relevance of Catalytic Anti-VIP Antibodies to the Airway
Published in Sami I. Said, Proinflammatory and Antiinflammatory Peptides, 2020
Information on catalytic antibodies has been obtained via two approaches. The first approach holds that immunization with transition state analogs is necessary to elicit catalytic antibody synthesis (reviewed in Ref. 12). The second approach has developed from empirical evidence that catalytic activities can be elaborated by entirely natural means in antibodies, as summarized below.
Consideration of Glutamine Synthetase as a Multifunctional Protein
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
The reaction mechanism for glutamine synthesis appears to occur by the formation of enzyme-bound intermediates, including γ-glutamyl phosphate.6,7 Evidence for the formation of the phosphorylated intermediate comes from several studies with analogs. One example is the use of L-methionine-SR-sulfoximine, a proposed transition-state analog, which is phosphorylated by glutamine synthetase in the presence of ATP and remains bound to the enzyme as the phosphorylated intermediate.12,15 L-methionine-SR-sulfoximine has been useful in locating the substrate binding sites. It appears that the oxygen atom of the sulfoximine binds to the site for the carboxyl oxygen atom of glutamate that does not get phosphorylated. The nitrogen atom of the sulfoximine binds at the site for the oxygen atom that is phosphorylated, and the methyl group of the methionine sulfoximine binds the ammonia binding site.7,14,16–21 This positioning allows the nitrogen atom of the sulfoximine to be phosphorylated.
Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections
Published in Expert Opinion on Therapeutic Targets, 2022
Christopher Schwake, Michael Hyon, Athar H. Chishti
Several chemical inhibitors of SPP have been developed (Table 1). A commonality between SPP inhibitors and the closely related HIV protease inhibitors is the peptide-mimic backbone and ketone functional groups that act as a transition state analogue (Table 1). (Z-LL)2 ketone was originally synthesized as a cysteine protease inhibitor and functions through reversible binding to the SPP active site through its ketone functional group [20]. The SPP inhibitors (Z-LL)2 ketone and LY411,575 inhibited SPP through a reporter-based assay with an IC50 of 140 nM and 730 nM, respectively [7]. As discussed below, the essentiality of parasite SPP has been demonstrated through inhibition by multiple SPP inhibitors as well as with HIV protease inhibitors. In addition to parasitic infections, many human viral infections utilize host SPP to process viral proteins for viral replication in the host. The focus of this review is to highlight the potential of targeting SPP in all major human infections caused by both parasites and viruses. Several parasite SPP genes are predicted but have not been validated biochemically, providing an exciting opportunity to develop specific novel inhibitors against these enzymes. Moreover, new evidence is emerging that viruses use host SPP to ensure protein maturation, viral replication, and immune evasion during infection.
Design, synthesis and characterization of enzyme-analogue-built polymer catalysts as artificial hydrolases
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Divya Mathew, Benny Thomas, Karakkattu Subrahmanian Devaky
The esterolytic and amidolytic reactions are debatably two major classes of reactions among the most common reactions found in nature and vital to the degradation of many biochemical substances. Enzymes play the important role as highly specific biological catalysts in biotechnology as well as in chemical reaction engineering. However, the drawbacks of these biomaterials are poor durability, relatively high costs of production, heat and pH sensitivity and incompatibility with organic solvents. Thus, molecular imprinting provides a prevailing, generic, superficial and cost-effective substitute for the preparation of artificial enzymes via the fabrication of specific recognition sites for a pre-determined template in a polymer matrix. Based on the theory of transition state stabilization, phosphonate monoester as a stable transition state analogue (TSA) is generally used as a template for hydrolytic reactions in molecular imprinting [8]. The imprint of the TSA acts like a catalytically active centre. This binding site shows its catalytic effect by reducing the activation energy of the specific reaction.
Characterization of the phosphotransacetylase-acetate kinase pathway for ATP production in Porphyromonas gingivalis
Published in Journal of Oral Microbiology, 2019
Yasuo Yoshida, Mitsunari Sato, Takamasa Nonaka, Yoshiaki Hasegawa, Yuichiro Kezuka
There are four crystallographically independent PgAck subunits in the asymmetric unit with distinct conformations, corresponding to the degree of opening and closing of the catalytic cleft (Figure 6(c)). Such conformational changes are a common feature of the acetate and sugar kinase/Hsc70/actin (ASKHA) superfamily [59]. Structural analysis of MtAck with transition state analogs ADP, AlF3 (a mimic of the meta-phosphate transition state), and acetate strongly suggest that catalysis proceeds via a direct in-line phosphoryl transfer mechanism [51]. ADP, AlF3, and acetate are aligned in a linear array in the cleft in MtAck, and the catalytic cleft is wide open to accommodate all three ligands. By contrast, the cleft of subunit D is almost closed in the PgAck structure determined without any ligands such as ADP, AlF3, and acetate. This structure likely represents complete cleft closure because there is a direct contact between residues Glu32 and Arg285 positioned on opposite sides of the interface of the two domains (Figure 6(b)). Comparison of the MtAck subunit with bound transition state analogs and subunit D of PgAck reveals a shift in the N-terminal domain of 22 Å (Cα-Cα distance between residue 37 of the two enzymes) upon cleft closure. This estimated value is larger than expected (≤15 Å) for MtAck and propionate kinase, other members of the ASKHA superfamily [60]. Therefore, these results strongly indicate a dramatic domain motion in PgAck during catalysis via a direct in-line phosphoryl transfer mechanism.