Proposed mechanism underlying the effects of leucine, tyrosine, arginine and homoarginine on the regulation of energy metabolism in GA1 cells.

<p>Lysine is first transported into the mitochondria via the ornithine carrier (ORC1) and subsequently degraded. Reacting with α-ketoglutarate (α-KG), lysine is converted to saccharopine, subsequently generating glutaryl-CoA, which can be catalyzed by GCDH to form acetyl-CoA. A defect in GCDH leads to glutaryl-CoA and GA accumulation. The counter-exchange of accumulated GA and α-KG through the oxodicarboxylate carrier (ODC) and oxoglutarate carrier (OGC) results in extreme depletion of α-KG. The reaction converting α-KG to succinyl-CoA in the TCA cycle is hindered; thus, the regeneration of oxaloacetate (OAA) is limited. The insufficient supply of OAA restricts acetyl-CoA from entering the TCA cycle. Acetyl-CoA is highly accumulated, and the TCA cycle is interrupted <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Zinnanti3" target="_blank">[15]</a>. The oxoglutarate dehydrogenase complex (OGDC) is located in the mitochondrial matrix and mediates the transformation of α-KG to succinyl-CoA and carbon dioxide in the TCA cycle <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Bunik1" target="_blank">[32]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Strumilo1" target="_blank">[33]</a>. Fumarase (FH), which is a mitochondrial enzyme, catalyzes fumarate to malate in the TCA cycle <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Bourgeron1" target="_blank">[34]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Isaacs1" target="_blank">[35]</a>. The pyruvate dehydrogenase complex (PDC) is able to channel glycolysis into the TCA cycle as a result of converting pyruvate to acetyl-CoA <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Strumilo2" target="_blank">[36]</a>. Acetyl-CoA can subsequently be converted to citrate in the presence of CS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110181#pone.0110181-Craig1" target="_blank">[37]</a>. Leucine, tyrosine and glucose can be converted to acetyl-CoA and enter the TCA cycle. Tyrosine can also generate fumarate. Arginine and homoarginine may inhibit mitochondrial transport of lysine at the mitochondrial carrier (ORC1).