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From

Dichloroacetate is a Novel Safe Treatment for Beta-ketothiolase Deficiency: Towards Better Therapeutic Outcomes (An Original Article)

Salah Mohamed El Sayed, Elsayed Abdelkreem, Moutasem Salih Aboonq, Sultan S. Al Thagfan, Yaser M. Alahmadi, Osama Alhadramy, Hussam Baghdadi, Mohammed Hassan, Faten M. Omran, Hytham Mahmoud Abdel-Latif, Wafaa Abdel-ziz, Azza Mahmoud Ahmed Abouelella, Amr El-Dardear, Mohamed Abdel-haleem, Elhussainy MA Elhussainy, Hassan El-Alaf, Manal Mohamed Helmy Nabo

International Journal of Clinical and Experimental Neurology. 2020, 8(1), 4-8 doi:10.12691/ijcen-8-1-2
  • Figure 1. Role of β-ketothiolase in ketone bodies synthesis (ketogenesis) and oxidation. DCA can prevent ketogenesis and inhibit further isoleucine catabolism (minimizing further acetoacetate formation and related ketoacidosis)
  • Figure 2. Biochemical bases and consequences of β-ketothiloase (BKT) deficiency. BKT plays a vital role in catabolism of isoleucine. BKT cleaves methylacetoacetyl CoA into acetyl CoA and propionyl CoA. Deficiency of BKT results in the accumulation of acetoacetate and lack of ketone bodies utilization. Fortunately, 1st step of isoleucine catabolism (transamination step) is reported to be indirectly inhibited by dichloroacetate (DCA). DCA inhibits first step of isoleucine catabolism preventing ketone bodies formation and subsequent refractory metabolic acidosis. That may suggest a promising role of DCA in treating BKT deficiency.
  • Figure 3. Transamination of isoleucine is vital for its catabolism. Alanine aminotransferase (ALT, GPT). The reaction is readily reversible. However, during amino acid catabolism, ALT enzyme functions in the direction of glutamate synthesis
  • Figure 4. Some acetate derivatives of biological importance. Acetyl CoA, acetoacetate, β-hydroxybutyrate and dichloroacetate (DCA) are acetate analogs. An evident pharmacological antagonism was reported between acetate and DCA. An evident pharmacological antagonism was reported between ketone bodies and DCA as regard effects on arterial blood pH where DCA treats metabolic acidosis