Succinic semialdehyde , and

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. 

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. 

The product of acetyl-CoA carboxylase reaction, malonyl-CoA, is reduced via malonate semialdehyde to 3-hydroxypropionate, which is further reductively converted to propionyl-CoA. Propionyl-CoA is carboxylated to (S)-methylmalonyl-CoA by the same carboxylase. (S)-Methylmalonyl-CoA is isomerized to (R)-methylmal-onyl-CoA, followed by carbon rearrangement to succinyl-CoA by coenzyme B 12-dependent methylmalonyl-CoA mutase. Succinyl-CoA is further reduced to succinate semialdehyde and then to 4-hydroxybutyrate. The latter compound is converted into two acetyl-CoA molecules via 4-hydroxybutyryl-CoA dehydratase, a key enzyme of the pathway. 4-Hydroxybutyryl-CoA dehydratase is a [4Fe-4S] cluster and FAD-containing enzyme that catalyzes the elimination of water from 4-hydroxybutyryl-CoA by a ketyl radical mechanism to yield crotonyl-CoA [34]. Conversion of the latter into two molecules of acetyl-CoA proceeds via normal P-oxidation steps. Hence, the 3-hydroxypropionate/4-hydroxybutyrate cycle (as illustrated in Figure 3.5) can be divided into two parts. In the first part, acetyl-CoA and two bicarbonate molecules are transformed to succinyl-CoA, while in the second part succinyl-CoA is converted to two acetyl-CoA molecules. 

Succinic semialdehyde was not detectable. Poly-7-glutamic acid showed a 54 % loss of glutamic acid a,/3-diaminopropionic acid was not determined, but no a,7-diaminobutyric acid could be found. The hydrolyzate gave a strong positive test for succinic semialdehyde, and the ammonia in the hydrolyzate indicated that the lost glutamic acid had undergone reaction as expected. 

GABA-T utilizes pyridoxal as the cofactor in the transamination reaction (Fig. 12-7A). Pyridoxal 5-phosphate (Vitamin B6, the cofactor) forms a Schiff base with GABA s NH2 group. The adjacent C-H bond has its proton abstracted by the enzyme reprotonation results in the tautomeric Schiff base, which on hydrolysis affords succinic semialdehyde and pyridoxamine. The pyridoxamine then forms a Schiff base with the carbonyl of a-ketoglutarate, reversing the steps, whereby hydrolysis of the tautomeric base yields l-glutamic acid, and the pyridoxamine, which has given up its NH2 function, reverts to the cofactor aldehyde form to repeat the cycle. 

Pseudomonas species degrade nicotine first to 6-hydroxypseudooxynicotine, or in the case of Pseudomonas putida to pseudooxynicotine. After oxidative deamination and oxidation of the aldehyde to the acid, the side-chain is cleaved off and yields succinic semialdehyde and 2,5-dihydroxypyridine, which is transformed into maleamic acid. 

An enzyme that transaminates y-aminobutyric acid has been shown to occur in brain and liver [IS, 14). The amino group acceptor is a-keto-glutaric acid and the reaction products are succinic semialdehyde and... 

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]. 

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. 

Biological. Heukelekian and Rand (1955) reported a 5-d BOD value of 1.31 g/g which is 58.7% of the ThOD value of 2.23 g/g. A Nocardia sp. isolated from soil was capable of transforming pyridine, in the presence of semicarbazide, into an intermediate product identified as succinic acid semialdehyde (Shukla and Kaul, 1986). 1,4-Dihydropyridine, glutaric dialdehyde, glutaric acid semialdehyde, and glutaric acid were identified as intermediate products when pyridine was degraded by Nocardiastiain Z1 (Watson and Cain, 1975). 

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. 

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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