A-Keto isovalerate

A 7-day-old girl has had a seizure. The mother explains that the baby has been vomiting and having difficulty feeding for the past 2 days. There is also a strange, sweet smell to her diapers. Physical examination is unremarkable, except for indications of dehydration. Serum test results show normal levels of glucose and ammonia. Urinalysis reveals the presence of a-keto-isocaproate and a-keto-isovalerate. 

A significant increase in the measured COj concentration was observed after the addition of 10 mmol/1 of a-keto-isovaleric acid (148% increase from baseline), a-keto-isocaproic acid (120%), phenylacetic acid (100%), DL-a-keto-P-methyl-A-valeric acid (100%), homogentisinic acid (50%), P-phenylpyruvic acid (45%), hydroxyphenyl acetic acid (32%), propionic acid (25%), ace-toacetic acid (25%), hydroxyphenyl pyruvate acid (23%), and 20 mmol/1 of hydroxyphenyl lactid acid (65%) or salicylic acid (76%). A significant decrease was observed after the addition of 20 mmol/1 of ascorbic acid (33%), DL- -hydroxybutyric acid (25%) or imidazole lactic acid (25%). No effect after the addition of 10 mmol/1 of imidazole-4-acetic acid, methylmalonic acid, 5-hy-droxyindole acetic acid or 20 mmol/1 arginosuccinic acid, Z.-(+)-hydroxybu-tyric acid (E525). 

The mechanism of fusel oil production from carbohydrates follows the typical Embden-Meyerhof-Pamas pathway to pyruvic acid. Pyruvic acid may be reacted with a second pyruvic acid to yield acetolactic acid. Acetolactic acid enters the valine-isoleucine biosynthesis pathway and is converted to a-keto isovaleric acid. The a-keto isovaleric acid may then be reduced to isobutyl alcohol or isobutyric... 

Active formaldehyde (hydroxymethyltetrahydrofolic acid, cf. Chapt. VI-5) is attached to a-keto-isovaleric acid (arising from valine by transamination) reduction of the keto group affords pantoic acid. ATP activates the carboxyl group, and the resulting pantoyl-AMP compound condenses with 3-alanine to yield pantothenic acid. 

Show a scheme for the reaction between thiamine diphosphate, lipoic acid and a-keto-isovaleric acid (structure in Figure 3.12). 

Thiamin functions as the coenzyme TDP in the metabolism of carbohydrates and branched-chain amino acids (a-keto-isocaproic, a-keto-yS-methyl valeric, and a-keto-isovaleric acids). In association... 

The three branched chain amino acids are normally metabolized as shown in Figure 6.2. Each amino acid is converted to the corresponding Of-keto acid by a transaminase specific for that amino acid. A solitary case of valinaemia is known, caused by lack of valine transaminase [76] the patient is mentally retarded. The three a-keto acids are decarboxylated by two (or possibly three) enzyme systems, one specific for a-keto-isovaleric acid, the other acting on a-keto-isocaproic and Q -keto-j3-methylvaleric acids [77, 78]. The reaction is complex, proceeding in three distinct steps [78] and requiring coenzyme A, thiamine pyrophosphate, lipoic acid and NAD. The end products are the co-enzyme A thio-esters of the branched chain fatty acids. 

Mutation of the dihydrolipoate reductase component impairs decarboxylation of branched-chain a-keto acids, of pyruvate, and of a-ketoglutarate. In intermittent branched-chain ketonuria, the a-keto acid decarboxylase retains some activity, and symptoms occur later in life. The impaired enzyme in isovaleric acidemia is isovaleryl-CoA dehydrogenase (reaction 3, Figure 30-19). Vomiting, acidosis, and coma follow ingestion of excess protein. Accumulated... 

Leucine is a branched chain-amino acid that is essential or required in the diet. Mitochondrial catabolism of excess leucine occurs by the pathway shown in Figure 20-3. The initial transamination step (removal of the amino group) is followed by a decarboxylation reaction to produce isovaleric acid. It is this decarboxylation of the a-keto analogs of the three... 

Even though leucine did not appear to be incorporated into a pyrazine molecule, the diversion of n-keto isovalerate to form leucine decreases the availability of this compound to form valine... 

A similar strategy has been developed in the avermectin system, using an S. avermi-tilis strain that lacks a branched-chain a-keto acid dehydrogenase (BCDH) activity. This dehydrogenase activity is required to produce the acyl-CoAs that are required for avermectin biosynthesis, and thus the BCDH mutant is unable to produce avermectin without the addition of exogenous fatty acids to the fermentation media. The addition of isobutyric acid or isovaleric acid allows the production of the natural avermectins, while the addition of non-natural carboxyhc acids results in the production of novel avermectins [92-94]. 

Volatile fatty acids p resent in wine may derive from the anabolism of lipids, resulting in compounds with even number of carbon atoms, by oxidative decarboxylation of a-keto acids or by the oxidation of aldehydes. Volatile fatty acids synthesised from a-keto acids are mainly propanoic add, 2-methyl-l-propanoic acid (isobutyric acid), 2-methyl-l-butanoic acid, 3-methyl-l-butanoic acid (isovaleric acid 3-methylbutyric add) and phenylacetic add. From lipid metabolism, the following fatty acids are reported butanoic add (butyric), hexanoic acid (caproic), odanoic acid (caprylic) and decanoic add (capric) (Dubois, 1994). Although fatty adds are charaderized by unpleasant notes (Table 1), only few compounds of this family attain its perception threshold. However, their flavour is essential to the aromatic equilibrium of wines (Etievant, 1991). 

The kutzneride cluster encodes three multidomain NRPS proteins, KtzE, KtzG, and KtzH, that make up the six required modules. KtzE activates o-MecPG and catalyzes its condensation with the hydroxy acid, which is activated by the A domain of KtzG. KtzG adenylates 2-keto-isovaleric acid and, after in situ reduction of the keto function by the KR domain, a methyltransferase forms the t-butyl group. Whether the... 

Fio. 7. Scheme of biosynthesis of valine and isoleucine. R tepresents a methyl group in valine and an ethyl group in isoleucine biosynthesis. I is pyruvate or a-keto-butyrate II is a-acetolactate or a-aceto-a-hydroxybutyrate HI is a-keto-/3-hydroxy> isovalerate or a-keto- -hydroxy- S-metbylvalerate IV is a,/ -dihydroxyisovalerate or a-0-dihydroxy- -methylvalerate V is a-ketoisovalerate or a-keto-d-methylvalerate and VI is valine or isoleucine. 

Fig. 3.3 Chromatogram of organic acids extracted from urine of a patient with branched-chain keto aciduria, separated as their methyl esters on 4 per cent QF-1 coated on Chromosorb G (HP, 100-120 mesh) at 79°C (isothermal). Peak identifications are 1, methyl 2-hydroxyisovalerate 2, methyl 2-ketO isovalerate 3, methyl 2-keto-3-methylvalerate 4, methyl 2-keto-isocaproate 5, methyl benzoate (internal standard). (Redrawn with modifications from Greer and Williams, 1967)...

XVIII has now been excluded,42 since the methyl glycoside of the sugar reacts rather rapidly with one mole of periodate per mole furthermore, in contrast to the behavior of mycaminose (XXI), no moiety with one carbon atom less has been isolated from the products of periodate oxidation. Oxidation of mycarose with hypoiodite affords a crystalline lactone with the empirical formula C7H12O4 this observation eliminates the possibility of the keto structure XX. Thus, mycarose appears to be a 2,6-dideoxy-3-C -methylhexose (XIX). In the original compound, the isovaleryl group must be esterified to the alcohol function at C4, since the methyl glycoside isovalerate obtained from carbomycin is only attacked by periodate after alkaline hydrolysis. 

Diabetes - insulin dependent Methyl malonic, propionic or isovaleric acidaemias Pyruvate carboxylase and multiple carboxylase deficiency Gluconeogenesis enzyme deficiency glucose-6-phosphatase, fructose-1,6-diphosphatase or abnormality of glycogen synthesis (glycogen synthase) Ketolysis defects Succinyl coenzyme A 3-keto acid transferase ACAC coenzyme A thiolase... 

Esters having two a-hydrogen atoms give poor yields of alkylated product partly because of their greater tendency for self-condensation to /3-keto esters (method 211). Ethyl isovalerate, however, has been ethylated in 33% yield by treatment with sodium triphenylmethide and ethyl benzenesulfonate. ... 

These results are contistent with the hypothesis that leucine is formed by a condensation of isovalerate, formed from pyruvate as established for valine, with an acetyl moiety, with the subsequent loss of a carboxyl group to yield keto leucine. This is then transaminsted to leucine. The... 

The isobutene metabolic pathway goes along the leucine biosynthesis pathway, from glucose to 2-ketoisocaproate (4-methyl-2-keto-pentanoate). The next two steps lead to isovalerate with a CO2 unit splitting off, which is then transformed to isobutene with cytochrome P450 as catalyst and additional CO2 equivalent separating (van Leeuwen et al. 2012). 

Fig. 10.1 Metabolites in the urine of an untreated patient with branched-chain keto aciduria (maple syrup urine disease). Extracted using ethyl acetate and separated as their trimethylsilyl-oxime derivatives on a 25 m SE-30 capillary column, using temperature programming from 80°C to 110°C at 0.5°C min and an injection split ratio 1 12 at a temperature of 250°C. The peaks marked R are due to solvent and reagents. Peak identifications are 1, lactic 2, 2-hydroxyisobutyric 3, 2-hydroxybutyric 4, pyruvic 5, 3-hydroxybutyric 6, 2-hydroxyisovaleric 7, 2-oxobutyric 8, 2-methyl-3-hydroxy-isovaleric 10, a and b, 2-oxoisovaleric 11, acetoacetic 12, 2-hydroxyisocaproic 13, 2-hydroxy-3-methyl- -valeric 14, 2-oxo-3-methyl-/i-valeric (14a L- 14b D-) 15, 2-oxoisocaproic acids. The internal standard was malonic acid. (Redrawn with modifications from Jellum etal., 1976)...

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