Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

Abstract

Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.

Keywords: branched-chain amino acids; cancer metabolism; epigenetics; metabolism.

Figure 1:. Schematic depicting BCAA metabolism and signaling

A) Pathway illustrating how branched chain amino acids (BCAA) (leucine, isoleucine, and valine) are broken down, and the regulation of BCAA breakdown by BCKDH. Branched chain amino acid transaminase 1 and 2 (BCAT1/2) transfers nitrogen to α-ketoglutarate (αKG) to produce glutamine and the specified branched chain keto acid (BCKA). These keto acids are then metabolized by branched chain alpha-keto acid dehydrogenase complex (BCKDH), to produce a branched chain acyl-CoA (R-CoA) that can be further metabolized in several steps to the TCA cycle intermediates acetyl-CoA and/or succinyl-CoA (from isoleucine and valine). BCKDH is comprised of three subunits; E1, E2, and E3, and activity of this enzyme is negatively regulated by phosphorylation as shown. Phosphorylation state of BCKDH is determined by the activities of branched chain keto acid dehydrogenase kinase (BCKDK) and PPM1K-protein phosphatase, Mg²⁺/Mn²⁺ dependent IK. B) Schematic showing how BCAA breakdown is related to signaling events and anabolic pathways that can play a role in cancer. ACLY, ATP-citrate lyase; OAA, Oxaloacetate.

Figure 2:. Systemic metabolism of BCAAs.

A) Dietary BCAA intake, as well as the balance between BCAA uptake and breakdown by tissues, combine to determine plasma BCAA levels. The liver is deficient in BCAT activity, and thus does not directly metabolize BCAAs. However, the liver can act on circulating branched chain keto acids (BCKAs), which are largely derived from the action of BCAT on protein derived BCAAs in skeletal muscle. This allows the liver to catabolize BCAAs or use them as a source of carbon to produce other molecules for the body such as fatty acids, glucose, and ketones. B) Deficiencies in the BCAA metabolism are responsible for inborn errors of metabolism. The relationship between each enzyme deficiency involving BCAA catabolism and the related disease is shown. C) Systemic metabolic diseases including insulin resistance and diabetes, obesity, and some cancer can all lead to changes in plasma BCAA levels, although the mechanistic underpinnings of these alterations remain an ongoing area of investigation.

Figure 3:. BCAA metabolism can modulate the epigenome.

A) Alterations in α-ketoglutarate (αKG) levels, which can be affected by BCAA metabolism, can influence global histone and DNA methylation patterns (as well as cytosine methylation, not shown) via effects on αKG-dependent dioxygenase activity (Gut and Verdin, 2013). Metabolites can also affect transcriptionally regulated expression of enzymes involved in BCAA breakdown. Mitochondrial acetyl-CoA from BCAA catabolism can contribute to cytoplasmic and nuclear pools of this metabolite, which provides the acetyl group for histone acetylation. Phosphorylation of the BCKDH E1 subunit to increase BCAA breakdown can affect ATP-citrate lyase (ACLY) activity as another way to alter acetyl-CoA levels in cells. 2-hydroxyglutarate (2-HG) produced by cancer associated mutations in isocitrate dehydrogenase (IDH1, shown; or IDH2, not shown) can also affect epigenetic regulation of gene expression, as well as inhibit the activity of BCAT1/2.