Alpha aminoadipine semi-aldehyde synthase, mitochondrial

The semi- aldehyde synthase alpha-aminoadipine protein catalyzes the first two stages of mammalian L-lysine cleavage via the saccharopine pathway in mitochondria , which is considered the main metabolic pathway for lysine cleavage in upper eukaryotes ^{[7] [8]} . Another way this enzyme focuses is the synthesis of glutaryl CoA from L-lysine ^[5] . Glutaryl-CoA can be an intermediate in a more extended pathway for the conversion / cleavage of L-lysine to Acetyl CoA.

Two notable components of the cleavage of L-lysine via the sugar-like pathway are the intermediate reaction / product of glutamate and possibly Acetyl CoA with carbon. Glutamate is an important substance in the body of the body from the group of neurotransmitters associated with Huntington’s disease ^{[9] [10]} . Acetyl CoA may have an even higher level of importance, acting as one of the integral components of citric acid / Krebs cycle, with the main function of delivering the acetyl group to be oxidized for energy production ^[11] . Thus, the function of alpha-aminoadipine semi-aldehyde synthase is associated with the levels of two integral compounds within the body.

First, the N-terminal portion of this enzyme, which contains the activity of lysine ketoglutarate reductase (LOR / LKR) ( Code number : 1.5.1.8), condenses lysine and 2-oxoglutarate with a molecule called saccharopine (reaction 1 in the figure on the right) ^{[ 3] [7]} . Then, the C-terminal part of this enzyme, which contains the activity of sugar-dehydrogenase (SHD) ( Code number : 1.5.1.9), catalyzes the oxidation of saccharopine with the formation of alpha-aminoadipid semi-aldehyde and glutamate (reaction 2 in the figure to the right) ^{[3] [7]} . Note: These reactions are inverse to the corresponding stages of lysine biosynthesis pathways present in yeast and fungi ^{[12] [13] [14]} .

These reactions can also be visualized in the form of balanced reactions:

N (6) - (L-1,3-dicarboxypropyl) -L-lysine + NADP ⁺ + H2O = L-lysine + 2-oxoglutarate + NADPH followed by

N (6) - (L-1,3-dicarboxypropyl) -L-lysine + NAD ⁺ + H2O = L-glutamate + (S) -2-amino-6-oxohexanoate + NADH ^[5] .

The native, human enzyme is bifunctional, like lysine ketoglutarate reductase or sugar-dehydrogenase (LKR / SHD) found in plants, and therefore it is believed to be similar in structure ^[12] . The bifunctionality of this enzyme comes from the fact that it performs two active functions, one at its C-terminus and the other at the N-terminus ^[3] . The C-terminal part of alpha-aminoadipine semi-aldehyde synthase contains SHD activity, and the N-terminal part contains LKR ^[15] . To date, the structure of alpha-aminoadipine semi-aldehyde synthase has not been determined ^[16] . The enzyme does not have a linker region present in plants, and the region of LKR activity is associated with the region of SHD activity, as in Magnaporthe grisea ^[15] .

Alpha aminoadipine semianaldehyde synthase is encoded by the AASS gene, and mutations of this gene lead to hyperlysinemia ^{[1] [3]} . This is characterized by impaired lysine breakdown, which leads to elevated levels of lysine in the blood and urine. An increase in lysine does not adversely affect the body ^[4] .

Hyperlisinemia is characterized by elevated plasma lysine levels, which exceeds 600 μmol / L and can reach up to 2000 μmol / L ^{[17] [18]} . This increase in lysine does not adversely affect the body ^[4] . The main reason lysine can replace some biochemical reactions. First, lysine can be used instead of ornithine in the urea cycle , which leads to homoarginine ^[19] . In addition, despite the fact that most mammals use the saccharopin pathway to break down lysine (path 1), the brain has an alternative path (path 2) that passes through the intermediate compound of L-pipecolic acid - both of which can be seen in figure ^[19] . It is worth noting that path 1 occurs in the mitochondria, while path 2 occurs in the peroxisome ^[8] . Considering other key enzymes in the pathway of L-lysine cleavage, ALDH7A1 is deficient in children with pyridoxine-dependent seizures ^[20] . GCDH deficiency of glutaric aciduria type 1 ^[21] . Intermediate 2-oxo-dipat is metabolized by 2-oxo-adipat dehydrogenase, similar to cirrhosis acid / Krebsky 2-oxoglutarate dehydrogenase enzyme complex ^[6] .

At present, two types of familial hyperlisinemia are described: type I is associated with a combined deficiency of two enzyme activities, LOR and SDH, while in familial hyperglycemia of type II, only the activity of sugar-dehydrogenase is disrupted ^{[22] [23]} . Type II hyperlysinemia is also referred to as saccharopinuria ^[6] .

An additional symptom associated with hyperlisinemia is a deficiency of dienoyl-CoA reductase, although this is a relatively recent discovery, and there are few publications supporting this ^[24] .