Methylmalonic acid

Methylmalonic acid (MMA) in semm is an estabUshed marker of cobalamine deficiency. MMA and other short-chain dicarboxyhc acids react with... 

To obtain a better understanding of the reaction mechanism, some compounds that are considered to he intermediates were subjected to the reaction. Various reaction courses can be considered as illustrated in Fig. 21. Path A a-Methyltropic acid is oxidized to a-phenyl-a-methylmalonic acid. Then, the malonate is converted to optically active a-phenylpropionate hy arylmalonate decarboxylase. In order to confirm this assumption, incubation of the malonic acid with Rhodococcus sp. was carried out. The result obtained was the total recovery of the substrate, indicating that no decarboxylase is present in this bacterium. Path B a-Methyltropic acid is converted to racemic a-phenylpropionic acid, which is deracemized to optically active propionic acid. To examine the possibility of this route, racemic a-phenylpropionic acid was subjected to the reaction to observe... 

Moller j, Rasmussen K, Christensen L (1999) External quality assessment of methylmalonic acid and total homocystein. Clin Chem 45 1536-1542. 

Consider obtaining homocysteine and methylmalonic acid levels. 

In patients with folic acid deficiency, methylmalonic acid may be normal, and homocysteine may be high. Monitor hemoglobin periodically, and reevaluate patients who fail to normalize hemoglobin levels after 2 months of therapy. 

In patients with vitamin B12 deficiency, methylmalonic acid and homocysteine levels may be high. Monitor for resolution of neurologic symptoms (i.e., confusion and paresthesias), if applicable, and Hgb levels periodically until the levels normalize. 

Schneede, J., and Ueland, P.M. (1992) Formation in an aqueous matrix and properties and chromatographic behavior of 1-pyrenyldiazomethane derivatives of methylmalonic acid and other short-chain dicarboxylic acids. Anal. Chem. 64, 315. 

Biochemical findings are variable. The blood cobala-min and folate levels often are normal. Patients often have homocysteinemia with hypomethioninemia, the latter finding discriminating this group from homocystinuria secondary to cystathionine- P-synthase deficiency. Urinary excretion of methylmalonic acid may be high, reflecting the fact that vitamin B12 serves as a cofactor for the methyl-malonyl-CoA (coenzyme A) mutase reaction. 

IGF insulin-like growth factor MMA methylmalonic acid... 

Vitamin deficiency can cause a megaloblastic anemia of the same type seen in folate deficiency (discussed in Chapter 17). In a patient with megaloblastic anemia, it is important to determine the underlying cause because Bjj defidency, if not corrected, produces a peripheral neuropathy owing to aberrant fatty acid incorporation into the myelin sheets associated with inadequate methylmalonyl CoA mutase activity. Excretion of methylmalonic acid indicates a vitamin Bjj deficiency rather than folate. 

Serine hydroxymethyl transferase catalyzes the decarboxylation reaction of a-amino-a-methylmalonic acid to give (J )-a-aminopropionic acid with retention of configuration [1]. The reaction of methylmalonyl-CoA catalyzed by malonyl-coenzyme A decarboxylase also proceeds with perfect retention of configuration, but the notation of the absolute configuration is reversed in accordance with the CIP-priority rule [2]. Of course, water is a good proton source and, if it comes in contact with these reactants, the product of decarboxylation should be a one-to-one mixture of the two enantiomers. Thus, the stereoselectivity of the reaction indicates that the reaction environment is highly hydro-phobic, so that no free water molecule attacks the intermediate. Even if some water molecules are present in the active site of the enzyme, they are entirely under the control of the enzyme. If this type of reaction can be realized using synthetic substrates, a new method will be developed for the preparation of optically active carboxylic acids that have a chiral center at the a-position. 

To screen a microorganism which has an ability to decarboxylate a-aryl-a-methylmalonic acids, a medium was used in which phenylmalonic acid was the sole source of carbon, because we assumed that the first step of the metabolic path would be decarboxylation of the acid to give phenylacetic acid, which would be further metabolized via oxidation at the a-position. Thus, a... 

Of course, the value of a-(o-chlorophenyl)-a-methylmalonic acid is not available because of its inactivity. If we suppose that its imaginary value is... 

Fig. 11. The potential energy diagram for C-C bond rotation in a-(o-chlorophenyl)-a-methylmalonic acid calculated with the HF/3-21G method...

Management is essentially the same as for folate deficiency but the site of the lesion, that may necessitate further investigation and treatment, needs accurate definition by means of the Schilling test. Additional useful determinations are homocysteine and methylmalonic acid levels. 

Vitamin B12 Low serum cobalamin (< 150 pmol/L) accompanied by increased serum homocysteine (> 13 Nnol/L), and increased serum (> 0.4 -mol/L) and urine (> 3.6 mmol/mol creatinine) methylmalonic acid... 

Furthermore, microbial decarboxylation of a-aryl-a-methylmalonic acids... 

In addition to the isomerization of glutamic acid, several other coenzyme B12-catalyzed reactions have now been discovered (I, 9, 15, 31, 51). The conversion of methylmalonic acid to succinic acid is very similar, and has been shown to occur through the migration of a carboxyl group, and postulated to involve free radical itermediates, as follows (15) ... 

Lenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonic acid metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, NY, pp 2165-2193... 

Fig. 3.1.6 GC-MS TIC organic acid profile of a patient with methylmalonic acidemia, a sample volume corresponding to 0.25 mg creatinine (standard procedure), b 10 x dilution (0.025 mg creatinine). Peak legend 1 methylmalonic acid (note the characteristic broad shape and spike, 2 urea, 3 citric acid, 4 2-methylcitric acid (two peaks). There was a fourfold difference in the measurement of methylmalonic acid excretion between the two analyses, with a substantial underestimation in the undiluted specimen...

Magera MJ, Helgeson JK, Matern D, Rinaldo P (2000) Methylmalonic acid measured in plasma and urine by stable-isotope dilution and electrospray tandem mass spectrometry. Clin Chem 46 1804-1810... 

When Rinaldo analyzed Ryan s blood serum, he found high concentrations of methylmalonic acid, a breakdown product of the branched-chain amino acids isoleucine and valine, which accumulates in MMA patients because the enzyme that should convert it to the next product in the metabolic pathway is defective. And particularly telling, he says, the child s blood and urine contained massive amounts of ketones, another metabolic consequence of the disease. Like Shoemaker, he did not find any ethylene glycol in a sample of the baby s bodily fluids. The bottle couldn t be tested, since it had mysteriously disappeared. Ri-naldo s analyses convinced him that Ryan had died from MMA, but how to account for the results from two labs, indicating that the boy had ethylene glycol in his blood Could they both be wrong ... 

One of the indicators of pernicious anemia, a disease caused by inability to absorb Bl2 through ihe gut wall, is an increase in excretion of methylmalonic acid as the body fails to convert it to succinic acid. 

Massart-Leen et al. (1981) analyzed bovine milk fat and goat milk fat for branched chain fatty acids. They did not find the same diversity of fatty acids in bovine as in goat milk fat and as previously reported. The authors suggested that the difference—the absence of branched chain acids other than iso and anteiso in bovine milk fat—could be caused by the relative inefficiency of the incorporations of methylmalonic acid into the biosynthetic pathway. 

In this hereditary disease up to 1 - 2 g of methylmalonic acid per day (compared to a normal of <5 mg/day) is excreted in the urine, and a high level of the compound is present in blood. Two causes of the rare disease are known/ One is the lack of functional vitamin B12-containing coenzyme. This can be a result of a mutation in any one of several different genes involved in the synthesis and transport of the cobalamin coenzyme.6 Cultured fibroblasts from patients with this form of the disease contain a very low level of the vitamin B12 coenzyme (Chapter 16), and addition of excess vitamin B12 to the diet may restore coenzyme synthesis to normal. Among elderly patients a smaller increase in methylmalonic acid excretion is a good indicator of vitamin B12 deficiency. A second form of the disease, which does not respond to vitamin B12, arises from a defect in the methylmalonyl mutase protein. Methylmalonic aciduria is often a very severe disease, frequently resulting in death in infancy. Surprisingly, some children with the condition are healthy and develop normally.3 1... 

Prepn is by treating methylmalonic acid dihydrazide with fuming nitric acid. The Diazide explds when rubbed or warmed (Ref 1, [272])... 

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