br Neurological development and BCAAs Glutamate is an

Neurological development and BCAAs Glutamate is an important excitatory neurotransmitter in the brain, and BCAAs (especially leucine) function to synthesize glutamate in astrocytes around neurons, since leucine enters the brain from the blood more rapidly than other BRD-9424 synthesis and provides ∼25% of all α-amino groups of glutamate [26]. Global BDK-KO (BDK-gKO) mice have been prepared and showed quite low levels of BCAAs in plasma and tissues including brain; the BCAA concentrations in the brains of BDK-gKO mice were ∼30% of control mice. These animals showed neurological abnormalities as judged by their performance of hind limb flexion over the life span and epileptic seizures after 6–7 months of age [27], suggesting that BCAAs have an important role in neurological function. Subsequent to the preparation of BDK-gKO mice, patients with homozygous BDK mutations were identified, and it was found that these patients showed markedly low levels of plasma BCAAs and suffered from autism, intellectual disability, and epilepsy [28,29]. Since some of the neurological phenotypes in BDK-gKO mice were reversed by dietary BCAA supplementation, it may be possible to treat patients with BDK mutations with BCAA supplementation [28].
Conflict of interest
Acknowledgement This work was supported by JSPS KAKENHI Grant Number JP17H03817 (to YS).
Introduction The metabolic requirements of proliferating cells, including cancer cells, differ from those of quiescent cells. Proliferating cells must acquire and process metabolites to fulfill the biosynthetic demands of replication, while maintaining energy and redox homeostasis. This presents particular challenges within the tumor microenvironment, which is often poorly vascularized and depleted of nutrients including molecular oxygen. Consequently, cancer cells utilize a broad range of strategies to obtain metabolic fuels, such that ‘use of opportunistic modes of nutrient acquisition’ was recently described as a hallmark of cancer metabolism [1]. A seminal discovery in the field of cancer metabolism was made in the 1920s by Otto Warburg, who observed that tumor tissues consume glucose much more rapidly than surrounding healthy tissue, and ferment glucose to lactate regardless of oxygen availability (aerobic glycolysis or the Warburg effect) [2]. Subsequently, Harry Eagle noted that optimal proliferation of certain cultured mammalian cell lines requires a several-fold molar excess of glutamine over any other amino acid [3]. Indeed, glucose and then glutamine are the most rapidly consumed nutrients by many cultured cancer cell lines [4,5], although altered metabolism of fatty acids, acetate, nucleotides, folate, proteins and several amino acids besides glutamine has also been reported [1]. Cancer cell metabolism has been targeted by drugs since the advent of modern chemotherapy. In the late 1940s, the antifolate aminopterin was used to induce remission in pediatric acute lymphoblastic leukemia (ALL) patients. Aminopterin, supplanted in the 1950s by the related drug methotrexate, competitively inhibits dihydrofolate reductase and thereby blocks recycling of tetrahydrofolate, a carrier of ‘one-carbon units’ that has essential roles in amino acid and nucleic acid metabolism [6]. Today antifolates, along with antipyrimidines and antipurines, are routinely used to treat a range of cancers, illustrating the feasibility of targeting metabolism for cancer therapy.
Cancer cell amino acid metabolism Another feature of amino acid metabolism in mammalian cells is a frequent apparent redundancy, with multiple enzymes catalyzing a given reaction. For instance, several enzymes convert glutamine to glutamate, including two mitochondrial glutaminases (GLS and GLS2) [7]. This inherent flexibility and redundancy present challenges for targeting amino acid metabolism, and therefore selection of patient groups, consideration of resistance mechanisms and identification of drug synergies will be crucially important for developing successful therapies. Techniques to image metabolism in vivo will also be valuable for identifying the tumors most likely to respond to treatment [8]. Below, we describe strategies for targeting amino acid metabolism, with a focus on glutamine and serine – the most rapidly consumed nutrients after glucose by many cultured cancer cell lines [4,5].