Leucine pathway

An example of the second type (b) is the mutation leading to loss of the keto-acid reductoisomerase (EC 1.1.1.86) in the parallel pathways leading to valine and isoleucine. This enzyme catalyses an isomerization coupled to a reduction, producing 2,3-dihy-droxyisovalerate in the valine pathway, or 2,3-dihy-droxy-3-methylvalerate in the leucine pathway. A single mutation of the gene for this enzyme produces val /ile doubly auxotrophic organisms. 

The disorders of the leucine pathway, including MSD, can usually be diagnosed by urine organic analysis. MSD is the only disorder of the pathway... 

Leucine, one of the twenty amino acids found in proteins, is metabolized by a pathway that includes the following step. Propose a mechanism. 

Scheme 9.38 Trichlorination of leucine with enzymes from the barbamide biosynthesis pathway (BarBl. BarB2 represent nonheme iron ketoglutarate-dependent halogenases).

Ganesan B, P Dobrowski, BC Weimer (2006) Identification of the leucine-to-2-methylbutyric acid catabolic pathway of Lactococcus lactis. Appl Environ Microbiol 72 4264-4273. 

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

Althoi alanine is the major gluconeogenic amino acid, 18 of the 20 (all but leucine and lysine) are also gluconeogenic. Most of these are converted by individual pathways to citric acid cycle intermediates, then to malate, following the same path from there to glucose. 

Figure 6.23 Positions in the gluconeogenic pathway where amino acids, fructose and glycerol enter the pathway. For details of the metabolism that provides the intermediates that actually enter the pathway from the amino acids, see Chapter 8. Not all of the carbon in some of the amino acids is incorporated into glucose (e.g. tryptophan). Two amino acids, leucine and lysine, do not give rise to glucose.

Capsaicinoids are synthesized by the condensation of vanillylamine with a short chain branched fatty acyl CoA. A schematic of this pathway is presented in Fig. 8.4. Evidence to support this pathway includes radiotracer studies, determination of enzyme activities, and the abundance of intermediates as a function of fruit development [51, 52, 57-63], Differential expression approaches have been used to isolate cDNA forms of biosynthetic genes [64-66], As this approach worked to corroborate several steps on the pathway, Mazourek et al. [67] used Arabidopsis sequences to design primers to clone the missing steps from a cDNA library. They have expanded the schema to include the biosynthesis of the key precursors phenylalanine and leucine, valine and isoleucine. Prior to this study it was not clear how the vanillin was produced, and thus the identification of candidate transcripts on the lignin pathway for the conversion of coumarate to feruloyl-CoA and the subsequent conversion to vanillin provide key tools to further test this proposed pathway. 

Yeast isopropylmalate isomerase of the leucine biosynthetic pathway, which catalyzes a totally analogous reaction to that of aconitase, converts 3-hydroxy-3-carboxy-4-methylpentanoate to 2-hydroxy-3-carboxy-4-methylpentanoate via an allylic intermediate. In its initial characterization by EPR spectroscopy, a high-field shift in its EPR signal from a g-average of 1.96 to 1.90 is seen upon addition of substrate (70). This result suggests that its mechanism is the same as that found for aconitase. 

Conceivably, lessons learned in yeast on internalization of membrane proteins are relevant to both the constitutive and the inducible pathways of receptor endocytosis in mammals. The constitutive pathway is the least understood, and it may bypass a requirement for ubiquitination by utilizing intrinsic di-leucine and other signals for protein internalization (Covers et al. 1998). In the ErbB family, the pathway may be exemplified by the relatively slow internalization rate of mutant RTKs, either the kinase- defective ErbB-3 (Baulida et al. 1996 Baulida and Carpenter 1997 Waterman et al. 1998), or artificial kinase-defective mutants (Chen et al. 1989 Felder et al. 1990). 

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

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