Succinic semialdehyd

Animals caimot synthesize the naphthoquinone ring of vitamin K, but necessary quantities are obtained by ingestion and from manufacture by intestinal flora. In plants and bacteria, the desired naphthoquinone ring is synthesized from 2-oxoglutaric acid (12) and shikimic acid (13) (71,72). Chorismic acid (14) reacts with a putative succinic semialdehyde TPP anion to form o-succinyl benzoic acid (73,74). In a second step, ortho-succmY benzoic acid is converted to the key intermediate, l,4-dihydroxy-2-naphthoic acid. Prenylation with phytyl pyrophosphate is followed by decarboxylation and methylation to complete the biosynthesis (75). 

Succinic semialdehyde (SSA) is synthesized in the mitochondria through transamination of y-aminobutyric acid (GABA) by GABA transaminase (GABA-T). Most of the SSA is oxidized by SSA dehydrogenase (SSA-DH) to form succinate, which is used for energy metabolism and results in the end products CO2 + H2O, which are expired. A small portion of SSA (<2%) is converted by SSA reductase (SSA-R) in the cytosol to GHB. GHB may also be oxidized back to SSA by GHB dehydrogenase (GHB-DH). 

Figure 11.3 Regulation of GAD during the synthesis of GABA. Active GAD (GAD-PLP) combines with glutamate (1) to form a complex (GAD-PLP-GLU). After decarboxylation (2) this yields GABA and GAD-PLP (3). The intermediate product (GAD-INT) can undergo an alternative reaction (4) to produce succinic semialdehyde (SSA) and pyridoxamine-5 -phosphate (PMP). PMP dissociates from GAD (5) leaving inactive enz5mie, which requires additional PLP to be reactivated (6), a process that is affected by ATP and inorganic phosphate...

Hydroxybutyric acid can also be directly incorporated [38], though some of it reacts with the corresponding enoyl-CoA. A more likely pathway proposed is via succinate semialdehyde, succinate, pyruvate, and acetyl-CoA, derived from 4-hydroxybutyrate, generally leading to a copolymer of 3-hydroxybutyryl and 4-hydroxybutyryl monomers from 4-hydroxybutyric acid [39]. 

GABA is metabolized by GABA-T to form succinic semialdehyde. To conserve the available supply of GABA,... 

Disorders of GABA Vitamin B6-dependent seizures Often an absence of succinic semialdehyde dehydrogenase Hypotonia, ataxia, mental retardation in older child. Increased urine 4-OH-butyric acid. Pyridoxine (B6-dependent disorder) Inhibitors of GABA transaminase... 

Succinic semialdehyde dehydrogenase deficiency. Patients have mental retardation, cerebellar disease, and hypotonia. They excrete large amounts of both succinic semialdehyde and 4-hydroxybutyric acid. There is no known therapy. 

Gupta, M Greven, R., Jansen, E. E., et al. (2002) Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma-hydroxybutyric aciduria). J. Pharmacol. Exp. Ther. 302,180-187. 

Schaller M, Schaffhauser M, Sans N, et al. Cloning and expression of succinic semialdehyde reductase from human brain. Identity with aflatoxin B1 aldehyde reductase. Eur J Biochem 1999 265(3) 1056-1060. 

Succinic acid, see 2-Chlorophenol. Cyclopentene, Maleic hvdrazide. 4-Nitrophenol, Phenol, 2,4.5-T Succinic semialdehyde, see Pyridine Succinyl-CoA, see Cyclohexane Sulfanilamide, see Asulam Sulfanilic acid, see Asulam Sulfonamide, see Prosulfuron Sulfonic acid, see Prosulfuron Sulfur, see Aldicarb. Benzene, Captan. Ferbam. 

GABA acts as an inhibitory transmitter in many different CNS pathways. It is subsequently destroyed by a transamination reaction (see Section 15.6) in which the amino group is transferred to 2-oxoglutaric acid, giving glutaric acid and succinic semialdehyde. This also requires PLP as a cofactor. Oxidation of the aldehyde group produces succinic acid, a Krebs cycle intermediate. 

This enzyme [EC 3.5.1.29] catalyzes the hydrolysis of 2-(acetamidomethylene)-succinate to yield acetate, succinate semialdehyde, carbon dioxide, and ammonia. 

This enzyme [EC 2.6.1.19] catalyzes the reversible reaction of y-aminobutyrate with a-ketoglutarate to yield succinate semialdehyde and glutamate. A number of enzyme preparations have been reported to also use )3-alanine, 5-aminopentanoate, and (i ,5)-3-amino-2-methylpropanoate as substrates. 

This enzyme [EC 1.1.1.61] catalyzes the reaction of 4-hydroxybutanoate with NAD+ to produce succinate semialdehyde and NADH. 

Valproic acid and its salts are a new group of antiepileptic drugs that differs from the known drugs both structurally and in terms of its mechanism of action. It is believed that it acts on the metabolism of the GABA system. Valproic acid has been shown to elevate the level of GABA in the brain by means of competitive inhibition of GABA transaminase and the dehydrogenase of succinic semialdehyde. 

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