Abstract
Cystathionine beta synthase (CBS) is the rate-limiting enzyme responsible for the de novo synthesis of cysteine. Patients with CBS deficiency have greatly elevated plasma total homocysteine (tHcy), decreased levels of plasma total cysteine (tCys), and often a marfanoid appearance characterized by thinness and low body-mass index (BMI). Here, we characterize the growth and body mass characteristics of CBS deficient TgI278T Cbs−/− mice and show that these animals have significantly decreased fat mass and tCys compared to heterozygous sibling mice. The decrease in fat mass is accompanied by a 34% decrease in liver glutathione (GSH) along with a significant decrease in liver mRNA and protein for the critical fat biosynthesizing enzyme Stearoyl CoA desaturase-1 (Scd-1). Because plasma tCys has been positively associated with fat mass in humans, we tested the hypothesis that decreased tCys in TgI278T Cbs−/− mice was the cause of the lean phenotype by placing the animals on water supplemented with N-acetyl cysteine (NAC) from birth to 240 days of age. Although NAC treatment in TgI278T Cbs−/− mice caused significant increase in serum tCys and liver GSH, there was no increase in body fat content or in liver Scd-1 levels. Our results show that lack of CBS activity causes loss of fat mass, and that this effect appears to be independent of low serum tCys.
Highlights
Cystathionine beta synthase (CBS) is the key regulatory enzyme for the transsulfuration pathway, which is responsible for the conversion of methionine to cysteine
The difference in size between control and Tg-I278T Cbs2/2 mice increased over time, primarily because Tg-I278T Cbs2/2 mice stopped putting on weight after 150 days, while the control animals kept growing throughout the entire period
The amount of lean mass in TgI278T Cbs2/2 animals was only slightly affected (9% and 14% less in females and males respectively, see Fig. 3B; regular water). These findings indicate that most of the size difference between Tg-I278T Cbs2/2 and control animals was due to difference in the animals fat mass
Summary
Cystathionine beta synthase (CBS) is the key regulatory enzyme for the transsulfuration pathway, which is responsible for the conversion of methionine to cysteine. The enzyme catalyzes the condensation of homocysteine with serine to create cystathionine, the precursor of cysteine. Cysteine is the rate-limiting amino acid in the biosynthesis of the major intracellular anti-oxidant thiol glutathione (GSH). In serum cysteine exists mostly in an oxidized state, cross-linked either to cysteine in proteins or other thiol containing amino acids. CBS deficiency ( known as classical homocystinuria) is the most common inborn error of sulfur metabolism and is characterized by extreme elevations of plasma total homocysteine (tHcy) and methionine along with low levels of plasma tCys [1]. The appearance of CBS deficient patients often resembles that of individuals with Marfan syndrome, characterized by arachnodactyly, scoliosis, low BMI, and reduced fat [2,3]
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