Figures & data
Figure 1. Function and structure of human glutaminases. (A) Catalytic function of glutaminase enzyme. (B) Two splice variants of GLS: KGA, the longer isoform with 18 exons, and GAC, the shorter isoform with 15 exons. (C) Two splice variants of GLS2: GAB, the longer isoform with 18 exons and LGA, the shorter isoform with 17 exons. (D, E) Structural domains of the splice variants of GLS and GLS2.
Figure 2. Cancer metabolism involving glutamine. Cancer cells transport glutamine through ASCT2. Glutamine thus entered is converted to glutamate through GLS and GLS2. The glutamate formed then moves into TCA cycle and supports the biosynthesis of nucleotides, proteins, and lipids. The regulators of glutaminase are marked in pink (Permission granted by Wang et al., 2020).
Figure 3. Various GLS inhibitors and the respective timeline of their discoveries. The orthosteric or competitive inhibitors, which include DON, acivicin, JHU-083 and DRP-104, are mentioned in the red boxes. BPTES, CB-839, IACS-6274, Compound 13b and Compound 13, which belongs to the class of allosteric inhibitors, are mentioned in the pink boxes. Compound 968 which is a GLS2 selective molecule is mentioned in the blue box.
Figure 4. Crystal structure of hKGA showing the allosteric and active sites. GLS forms a tetramer and the interface of dimers forms the allosteric site. Glutamine is the substrate for the active site and BPTES, a GLS inhibitor, occupies the allosteric site (Permission granted by the American Chemical Society from L. Chen & Cui, 2015).
Table 1. GLS inhibitors under development.
Figure 5. Glutaminase inhibitor resistance through alternate metabolic pathways. Targeting glutaminase and alternate metabolic pathways prevent the TCA cycle, which results in the deprivation of energy and building blocks required for cell growth. Inhibitors are marked in red and the alternate pathways involved in resistance of GLS inhibitors is marked in purple. (Re-drawn with permission from Wang et al., 2020).
