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1. A semi-synthetic vitamin B12-deficient diet, based on soya flour, is described. When supplemented with cydnocobalamin the diet appeared to be adequate for growth and reproduction in the rat.2. Compared with their litter-mates on the supplemented diet, rats fed on the deficient diet from weaning showed reduced levels of vitamin B12 activity in the plasma and tissues, but their growth rates were unaffected unless they were bred from mothers that had been given the deficient diet since mating.3. When they were reared on the deficient diet, rats bred from mothers on the deficient diet since mating excreted much more methylmalonic acid in the urine than their litter-mates on the supplemented diet. There was wide variation in the level of excretion, both between different animals and from day to day in the same animal.4. Starvation for more than 16 h caused a marked depression in the amount of methylmalonic acid excreted by rats on the deficient diet.5. Intraperitoneal injection of sodium propionate into deficient animals after starvation for 24 h caused increased excretion of methylmalonic acid during the following 16 h of continued starvation. Isoleucine had a similar but smaller effect.6. Tested in the starved animal, sodium propionate and valine given either by intra- peritoneal injection or by mouth, and isoleucine given intraperitoneally, caused increases in the excretion of methylmalonic acid. In contrast, methionine had no effect and threonine only a slight effect.

1. Kidney-cortex slices and the perfused livers of vitamin B(12)-deficient rats removed propionate from the incubation and perfusion media at 33 and 17% respectively of the rates found with tissues from rats receiving either a normal or a vitamin B(12)-supplemented diet. There was a corresponding fall in the rates of glucose synthesis from propionate in both tissues. 2. The addition of hydroxocobalamin or dimethylbenzimidazolylcobamide coenzyme to kidney-cortex slices from vitamin B(12)-deficient rats in vitro failed to restore the normal capacity for propionate metabolism. 3. Although the vitamin B(12)-deficient rat excretes measurable amounts of methylmalonate, no methylmalonate production could be detected (probably because of the low sensitivity of the method) when kidney-cortex slices or livers from deficient rats were incubated or perfused with propionate. 4. The addition of methylmalonate (5mm) to kidney-cortex slices from rats fed on a normal diet inhibited gluconeogenesis from propionate by 25%. 5. Methylmalonate formation is normally only a small fraction of the flux through methylmalonyl-CoA. This fraction increases in vitamin B(12)-deficient tissues (as shown by the urinary excretion of methylmalonate) presumably because the concentration of methylmalonyl-CoA rises as a result of low activity of methylmalonyl-CoA mutase (EC 5.4.99.2). Slow removal of methylmalonyl-CoA might depress propionate uptake owing to the reversibility of the steps leading to methylmalonyl-CoA formation.

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