Intervention through Enzymes

The glyoxalase system is able to convert a-oxoaldehydes into the corresponding a-hydroxyacids, a reaction that lowers oxidative stress. Glyoxalase I (EC 4.4.1.5) mimetic activity has been associated with imidazole derivatives, such as histidine and camosine, and their activity in liberating lactic acid from. S -lactoylglutathionc has been confirmed.613 However, mammalian tissue displays about 4000 times this activity. 

The first report of an enzyme capable of catabolysing Amadori compounds is by Horiuchi el al.,6U who were able to purify it about 40-fold to a single protein band 

Takahashi et al.61s further identified the primary structure by preparing a cDNA library from A. fumigatus induced with fructosylpropylamine and isolated a clone using a polyclonal Amadoriase II antibody. The structure comprised 438 amino acid residues, corresponding to 48.798 kDa. The identity of the Amadoriase n cDNA was further confirmed by expression in Escherichia coli cells with an inducible expression system. Northern-blotting analysis showed that Amadoriase II was induced by fructosylpropylamine in a dose-dependent manner. The sequence determined showed the enzyme to represent a new family of mammalian enzymes. The sequence exhibited 82 and 36% identity and 92 and 65% similarity, respectively, with the two sequences determined by Yoshida et al.616 Amadori products have been implicated in the formation of H202, but the in vivo mechanism needs to be elucidated further. 

Although metal-catalysed oxidation can lead to glucosone and H202, the existence of amadoriases suggests that Amadori products might well be involved. 

Stopped-flow kinetic studies of Amadoriase I using fructosylpropylamine and oxygen as substrates in 10 mM Tris hydrochloride buffer (pH 7.9) at 4 °C pointed to the pyranose form as being the active configuration. The redox potentials were found to be + 48 and -52 mV for the oxidised enzyme/anionic quinone and anionic semi-quinone/reduced enzyme reactions, respectively, at pH 7.0 and 25 °C.620 

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Monnier et al.519 had further comments on each. In this chapter, attention is paid especially to trapping agents and intervention through enzymes, ending up with mention of a recently demonstrated hypoglycaemic agent. 

Enyzme catalysis is thus essential for all life. Hence the selective inhibition of critical enzymes of infectious organisms (e.g., viruses, bacteria, and multicellular parasites) is an attractive means of chemotherapeutic intervention for infectious diseases. This strategy is well represented in modem medicine, with a significant portion of antiviral, antibiotic, and antiparasitic drugs in clinical use today deriving their therapeutic efficacy through selective enzyme inhibition (see Table 1.1 for some examples). 

The folate pathway is one in which selective chemotherapeutic intervention has been very successful, and a number of drugs acting through this pathway are in current use. This is because of the fact that mammals receive FA from their diet and convert it into dihydrofolic acid (DHFA) and tetrahydrofolic acid (THFA), which give rise to folate cofactors. The bacteria and protozoans, on the other hand can not effectively utilize FA to get their requirements of DHFA and THFA. Consequently, these organisms synthesize DHFA de novo (for details, see Chapter 13). Further the affinity of the enzymes involved from different sources (mammalian, bacterial and protozoan) for different classes of inhibitors is quite different, which has resulted in the development of drugs with selective action. 

ESKD (see Chap. 44), necessitating dialysis or transplantation for survival (see Chaps. 45 and 87). The rate of progression can be slowed and in some cases halted through dietary modification and blood pressure control, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker therapy, and improved glucose control in patients with type I diabetes mellitus (see Chap. 43). The efficacy of these interventions is optimally assessed with serial measurements of accurate and sensitive indices of GFR such as iohexol, iothalamate, or radioisotope clearances. ... 

As described above, KMO catalyzes the hydroxylation at the third position of kynurenine. The KMO enzyme is thus at a key position of the pathway as its activity determines the level of flux through the two arms of the pathway. KMO inhibition is expected to be beneficial in neurodegenerative disease as this would increase the availability of KYN to KATII, and thus achieves a shift away from QUIN and 3-HK production to an increase in KYNA production. Thus, KMO has been considered the most relevant target for therapeutic intervention in the KP for CNS disease [1]. 

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