Lysine Degradation in Human Liver
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Lysine Degradation in Human Liver

In humans, Lysine is an essential amino acid, and there is no Lysine biosynthetic machinery. However, humans do degrade Lysine. Lysine is incorporated to Collagen, one of the most important components of Connective tissue and its supply is therefore required during embryonic development and early childhood (Ref.1). It is also important for Carnitine Synthesis. The main catabolic pathway for Lysine, via Saccharopine (e-N-(L-Glutaryl-2)-L-lysine), is a mitochondrial pathway leading to the formation of Acetyl-CoA (Acetyl-Coenzyme-A). Another Lysine degradation mechanism that is the Peroxisomal Pathway, via Pipecolic Acid is of less physiological importance and is mainly active in brain. The existence of two minor pathways for Lysine degradation, the Acetyllysine Pathway and the Lysine-Urea Cycle, remains to be demonstrated (Ref.2).

The Saccharopine Pathway, the main metabolic route for Lysine degradation in upper eukaryotes, proceeds via formation of Lysine-Alpha-Ketoglutarate adduct Saccharopine and predominates in human liver. Its first two reactions are catalysed by the enzymatic activity of AASS (Aminoadipate-Semialdehyde Synthase) which condenses Lysine and Alpha-Ketoglutarate to form Saccharopine. Saccharopine is then subsequently oxidized by the dehydrogenase activity of the same enzyme to produce Alpha-Aminoadipate-6-Semialdehyde and Glutamate, followed by a conversion of Alpha-Aminoadipate-6-Semialdehyde to Alpha-Aminoadipate by AASDH (Alpha-Aminoadipate Semialdehyde Dehydrogenase) (Ref.2). The next step is a PLP (Pyridoxal-5’-Phosphate)-dependent transamination in which AADAT (Aminoadipate Aminotransferase), a PLP cofactor-dependent enzyme converts Alpha-Aminoadipate to Alpha-Ketoadipate. This follows the oxidative decarboxylation of Alpha-Ketoadipate by BCKDH (Branched-Chain-Keto Acid Dehydrogenase) Complex to form Glutaryl-CoA (Glutaryl-Coenzyme-A), releasing the Carboxyl group as CO2 and producing the Acyl-CoA derivative. Glutaryl-CoA undergoes dehydrogenation by FAD (Flavin Adenine Dinucleotide) with the liberation of two moles of CO2 (Carbondioxide) to form Crotonyl-CoA (Crotonyl-Coenzyme-A). This step is catalyzed by GCDH (Glutaryl-Coenzyme-A Dehydrogenase) and FAD is reduced to FADH2 (Ref.3). Crotonyl-CoA undergoes hydration by ECHS1 (Enoyl Coenzyme-A Hydratase Short Chain-1, Mitochondrial) to form Beta-Hydroxybutyryl-CoA (Beta-Hydroxybutyryl-Coenzyme-A). Dehydrogenation of Beta-Hydroxybutyryl-CoA leads to the formation of Acetoacetyl-CoA (Acetoacetyl-Coenzyme-A) catalyzed by Beta-Hydroxyacyl-CoA Dehydrogenase. In this step NAD+ (Nicotinamide Adenine Dinucleotide) is reduced to NADH. Penultimate step includes conversion of Acetoacetyl-CoA to HMG-CoA (Hydroxymethylglutaryl-Coenzyme-A) by HMG-CoA Synthase. Finally action of HMGCL (Hydroxymethylglutaryl-CoA Lyase Mitochondrial) upon HMG-CoA leads to the formation of Acetoacetate and release of Acetyl-CoA. The last two steps are standard reactions in Ketone body formation (Ref.4).

Genetic disorders in Lysine degradation mainly results in Familial Hyperlysinemia, Saccharopinuria and Maple Syrup Urine Disease. Familial Hyperlysinemias are Autosomal Recessive Disorders in the oxidative degradation of Lysine (Ref.3). Hyperlysinemia and Saccharopinuria occur due to mutation at a single locus, that codes for the bi-functional enzyme AASS. In Maple Syrup Urine Disease the Alpha-Keto Acids get accumulated in the urine. Other varieties of inborn errors of Lysine Catabolism include Amino and Ketoadipic Aciduria and Glutaric Aciduria. Genetic Counseling and/or Neonatal screening program might envisage the possibility of changing the natural course of such diseases (Ref.4).