Propargylglycine inhibits hypotaurine/taurine synthesis and elevates cystathionine and homocysteine concentrations in primary mouse hepatocytes

Our investigation showed that hepatocytes isolated from cysteine dioxygenase knockout mice (Cdo1(−/−)) had lower levels of hypotaurine and taurine than Cdo1(+/+) hepatocytes. Interestingly, hypotaurine accumulates in cultured wild-type hepatocytes. dl-propargylglycine (PPG, inhibitor of cystathionine γ-lyase and H(2)S production) dramatically decreased both taurine and hypotaurine levels in wild-type hepatocytes compared to untreated cells. Addition of 2 mM PPG resulted in the decrease of the intracellular taurine levels: from 10.25 ± 5.00 observed in control, to 2.53 ± 0.68 nmol/mg protein (24 h of culture) and from 17.06 ± 9.40 to 2.43 ± 0.26 nmol/mg protein (control vs. PPG; 48 h). Addition of PPG reduced also intracellular hypotaurine levels: from 7.46 ± 3.55 to 0.31 ± 0.12 nmol/mg protein (control vs. PPG; 24 h) and from 4.54 ± 3.20 to 0.42 ± 0.11 nmol/mg protein (control vs. PPG; 48 h). The similar effects of PPG on hypotaurine and taurine levels were observed in culture medium. PPG blocked hypotaurine/taurine synthesis in wild-type hepatocytes, suggesting that it strongly inhibits cysteinesulfinate decarboxylase (pyridoxal 5′-phosphate-dependent enzyme) as well as cystathionine γ-lyase. In the presence of PPG, intracellular and medium cystathionine levels for both wild-type and Cdo1(−/−) cells were increased. Addition of homocysteine or methionine resulted in higher intracellular concentrations of homocysteine, which is a cosubstrate for cystathionine β-synthase (CBS). It seems that PPG increases CBS-mediated desulfhydration by enhancing homocysteine levels in hepatocytes. There were no overall effects of PPG or genotype on intracellular or medium glutathione levels

The First International Mini-Symposium on Methionine Restriction and Lifespan

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan (Orentreich et al., 1993). Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases (Richie et al., 1994; Miller et al., 2005; Ables et al., 2012; Sanchez-Roman and Barja, 2013). We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed. The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies (Figure 3)

Biochemical, physiological, and molecular aspects of human nutrition, 3rd ed./ Stipanuk

xix, 948 hal.: ill, tab.; 28 cm

Biochemical, physiological, and molecular aspects of human nutrition, 3rd ed./ Stipanuk

xix, 948 hal.: ill, tab.; 28 cm

Metabolism of cysteine to taurine by rat hepatocytes.

During the past two decades, many investigators have assumed that the major locus of regulation of cysteine catabolism is the partitioning of cysteinesulfinate between its decarboxylation and transamination pathways. Hepatic cysteinesulfinate decarboxylase activity correlates well with the capacity of animals to synthesize taurine1–4, and low cysteinesulfinate decarboxylase activity in the cat has been associated with its nutritional requirement for dietary taurine5. More recent studies in our laboratory have indicated that cysteinesulfinate-independent pathways also play a major role in cysteine metabolism6,7. In contrast to cysteinesulfinate-dependent metabolism of cysteine, which leads to both taurine and sulfate production, the cysteinesulfinate-independent pathways all result in release of reduced inorganic sulfur and its subsequent oxidation to sulfate. This evidence revealing a contribution of cysteinesulfinate-independent pathways to cysteine catabolism suggested that partitioning of cysteine between cysteinesulfinate formation and metabolism by cysteinesulfinate-independent pathways may also be important in the regulation of cysteine metabolism to taurine