Structural Determinants for Substrate Selectivity in Guanine Deaminase Enzymes of the Amidohydrolase Superfamily

Abstract

Human albumin infusion for treating oedema in people with nephrotic syndrome (Review)

Real-Time Monitoring of Human Guanine Deaminase Activity by an Emissive Guanine Analog

“…As stated, the presence of the nitrogen at a position equivalent to N7 in the purine skeleton endows tz G N , the isothiazole purine surrogate, with substrate recognition features that appear lacking in th G N . While comprehensive investigations of the GDA substrate scope have not been pursued, previous substrate and inhibitor analyses of aminohydrolase isoforms suggest that the O6, N3, and N7 points of contact are important for substrate recognition. ,,, Intriguingly, while tz G N retains these contact points, it is lacking the NH group found in the purine’s 9 position. Previously reported inhibitors, such as valciclovir and derivatives of azepinomycin, containing substituents at the N9 position suggest GDA can tolerate diverse groups at that position, which may explain the high tolerance and the native deamination rate displayed by tz G N . , …”

“…Guanine deaminase (GDA), a hydrolytic zinc-based enzyme, converts guanine to xanthine. , Recent observations have shown it impacts neuronal morphology , and implicated GDA in traumatic brain injury, memory dysfunction, and psychiatric diseases . The study of human GDA, from the aminohydrolase superfamily, has remained somewhat sparse compared to other deaminases, including adenosine deaminase (ADA) , and cytidine deaminase (CDA), which convert adenosine to inosine and cytidine to uridine, respectively.…”

“…Applying such approaches to nucleobase-processing enzymes such as human GDA represents, however, a minimally explored territory, as highly emissive nucleobase analogs have not been broadly tested and scrutinized as substrates. , The lack of the rather large and contact forming d -ribose residue presents the challenge of altering guanine without disturbing contacts at the active site of such a potentially fastidious nucleobase-processing enzyme . We therefore set out to investigate two emissive nucleobase analogs, thieno­[3,4- d ]­pyrimidine ( th G N ) and isothiazole­[4,3- d ]­pyrimidine ( tz G N ) (Figure c), and demonstrate that while the former is not a viable substrate, tz G N does undergo facile GDA-mediated deamination to yield the fluorescently distinct xanthine analog, tz X N .…”

Unfolding New Roles for Guanine-Based Purines and Their Metabolizing Enzymes in Cancer and Aging Disorders

“…GBPs share many structural and functional similarities with ABPs (Santos et al, 2006): they are released by many cell types, interconverted by soluble and membrane-bound ecto-enzymes and either taken up by selective nucleoside transporters or further metabolized up to the formation of uric acid (Zimmermann and Braun, 1996). Specifically, extracellular GUO is converted by purine nucleoside phosphorylase (PNP) to GUA that, in turn, is metabolized to xanthine (XAN) by guanine deaminase (GDA) (Yuan et al, 1999;Giuliani et al, 2016;Shek et al, 2019).…”

A drought‐responsive rice amidohydrolase is the elusive plant guanine deaminase with the potential to modulate the epigenome

“…(Dahncke and Witte 2013 ). Similarly, a guanine deaminase, which catabolizes guanine to xanthine in animal tissues and microorganisms is also an amidohydrolase (Shek et al, 2019 ). In plants the biochemical activity of guanine deaminases has been characterized in tea and coffee leaves where the product of guanine catabolism, xanthine, is a precursor for theine and caffeine (Negishi et al, 1994 ; Ashihara et al, 2008 ).…”