Abstract
Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.
Highlights
The identification of the Krebs–Henseleit urea cycle in the early 1930s highlighted the importance of arginase, a manganese-containing enzyme that catalyzes the conversion of L-arginine to urea and L-ornithine
The design of isoform-specific arginase inhibitors has shown to be challenging since the difference between the active-site of Arg1 and Arg2 is limited to minor structural variations (Figure 2A)
The development of arginase inhibitors by structure-based drug design resulted in several potent compounds
Summary
The identification of the Krebs–Henseleit urea cycle in the early 1930s highlighted the importance of arginase, a manganese-containing enzyme that catalyzes the conversion of L-arginine to urea and L-ornithine. TDiteysipsitsehabreeindgbeynbcootdhedisobfyordmifsfe, raenndt galelnaecst,ivaep-psritoexrimesaidteuleys6i1n%voolvf ethdeinamsuinbostaractide sequence identity is shared by both isoforms, and all active-site residues involved in substrate binding, as well as the binuclear Mn2+ cluster core, are strictly conserved (Figure 2A). These Mn2+ ions are approximately 3.3 Å apart, bridged by an OH− ion, and mainly surrounded by negatively charged. Alongside the importance of a balanced M1/M2 polarization sequence, to maintain homeostasis, and of a regulatory feedback pathway (e.g., type 1 helper T cells stimulate NO levels but can be inhibited by this gas to prevent an exacerbated immune response), there is a microenvironment-dependent multifactorial signaling cascade able to regulate macrophage plasticity and to promote the development and differentiation of T cells and cytokines. The mapping of arginase expression holds high potential as a molecular imaging biomarker for the identification and follow up of neoplastic, inflammatory, and allergic disorders
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
