Valine, load

Methylmalonate semialdehyde dehydrogenase deficiency [8] has been described in a single patient. This patient, a boy, came to attention because of an elevated concentration of methionine on routine neonatal screening. The value exceeded 1000 imol/l. By 4 years of age he had developed normally. A valine load was followed by an increase in 3-hydroxyisobutyric acid excretion. Incubation of fibroblasts from the patient with 2-valine or p-[1- C]-alanine led to no production of C02 from valine and very little from )ff-alanine in contrast to control cells. 

A serum concentration of vitamin B below llOpmol/L is associated with megaloblastic bone marrow, incipient anaemia and myelin damage. Below 150pmol/L there are early bone marrow changes, abnormalities of the dUMP suppression test (section 11.11.6.2) and methylmalonic aciduria after a valine load (section 11.10.2). 

Enantiomer separation factors (a values) for valine and phenylalanine as well as their esters of 5-10 for phenylalanine and 4-10 for valine have been shown at the 0.1-1 g ChiraLig scale. These a values vary as a function of solvent and other loading matrix factors (pH, salts, etc.). However, all of these cases show a values high enough to obtain reasonable enantiometric purity in less than or equal to three stages. The system with a value of = 6 for the valine methyl ester enantiomers has the ability to load the valine onto the resin in H,0 containing LiClO and also to... 

Table 8-2. Singe column (3.9 g ChiraLig ) loading curve of 24 mM D-methyl ester valine versus 25 mM L-methyl ester valine in 3 M LiClO and 0.1 M HCIO at a flowrate of 0.4 ml min . ...

L-valine. The application of these ligands to the asymmetric addition of ZnEt2 to aldehydes provided the corresponding products with excellent enan-tioselectivities as high as 99% ee in almost all cases and with a catalytic loading as little as 0.02 mol% of the ligand depicted in Scheme 3.9. 

A vast array of chiral catalysts have been developed for the enantioselective reactions of diazo compounds but the majority has been applied to asymmetric cyclopropanations of alkyl diazoacetates [2]. Prominent catalysts for asymmetric intermolecular C-H insertions are the dirhodium tetraprolinate catalysts, Rh2(S-TBSP)4 (la) and Rh2(S-DOSP)4 (lb), and the bridged analogue Rh2(S-biDOSP)2 (2) [7] (Fig. 1). A related prolinate catalyst is the amide 3 [8]. Another catalyst that has been occasionally used in intermolecular C-H activations is Rh2(S-MEPY)4 (4) [9], The most notable catalysts that have been used in enantioselective ylide transformations are the valine derivative, Rh2(S-BPTV)4 (5) [10], and the binaphthylphosphate catalysts, Rh2(R-BNP)4 (6a) and Rh2(R-DDNP)4 (6b) [11]. All of the catalysts tend to be very active in the decomposition of diazo compounds and generally, carbenoid reactions are conducted with 1 mol % or less of catalyst loading [1-3]. 

The Raillard group at Affymax developed a multigram synthesis of a 2,5-diketopiperazine and other heterocyclic systems by employing a high-load Merri-field resin transformed into polymer-supported valine, which was used as the amino component in an Ugi-4CR to gave the target diketopiperazine 137 after cleavage of 136 from the resin [77] (Scheme 2.49). 

Similar displacement chromatographic separations have been obtained for other samples as well including naphthol iscmers (67), nitroaniline iscmers (67), nitrophenol iscmers (67), the cis- and trans-iscmers of 3-hexen-l-ol (68), and the enantiomers of mephobarbital (69), hexobarbital (69), dansyl leucine (69) and dansyl valine (69). Sample loadings on the 4.6 mn ID. analytical columns varied between 0.1 milligram and 60 milligram the concentration of the separated solutes in the collected fractions ranged from 0.1 nM to 10 nM. 

Methylmalonyl-CoA mutase is a cobalamin-linked enzyme of mitochondria that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. A reduction of this enzyme due to vitamin B12 deficiency will result in a metabolic block with the urinary excretion of methylmalonic acid, and the measurement of this metabolite has been used to confirm a deficiency of vitamin B12. The test has also been useful in investigating rare abnormalities of this enzyme that result in the excretion of methylmalonic acid in the presence of adequate vitamin B12. Given an oral loading dose of valine or isoleucine will increase the urinary excretion of methylmalonic acid in patients with a vitamin B12 deficiency (G4). However, Chanarin and his colleagues (CIO) found that one-quarter of their patients with pernicious anemia excreted a normal concentration of methylmalonic acid even after a loading dose of valine. Normal subjects excrete up to 15 mg of methylmalonic acid in their urine over a 24-hour period (Cll). 

As discussed in Section 10.8.2, moderate vitamin B12 deficiency results in increased accumulation of methylmalonyl CoA, and methylmalonic aciduria and methylmalonic acidemia. This can be exploited as both a means of detecting subclinical deficiency and monitoring vitamin B12 status in patients with pernicious anemia who have been treated with parenteral vitamin. As they become depleted, the excretion of methylmalonic acid, especially after a loading dose of valine, will provide a sensitive index of depletion of vitamin Bi2 reserves. 

Methylmalonyl CoA mutase is especially sensitive to vitamin B12 depletion, so methylmalonic aciduria is the most sensitive index of vitamin B12 status. Folate deficiency does not cause methylmalonic aciduria. However, up to 25% of patients with confirmed pernicious anemia excrete normal amounts of methylmalonic acid, even after a loading dose of valine (Chanarin et al., 1973). 

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