Dietary Effects of Sulfur Amino Acid Depletion and Repletion on Glutathione and Cysteine Pools.

The long-term objectives of this research are to improve the definition of optimal human SAA intake. This will include defining Dietary Reference Intakes (DRI), estimated average requirement (EAR), and the upper limit (UL) of intake by improving the understanding of the physiologic and pathologic responses to variatiation in SAA intake. Using high-resolution 1H-NMR, we plan on developing comprehensive metabolic profiles that can indicate when SAA intake is inadequate.

The specific aims of the current protocol are:

1. To determine whether steady-state GSH/GSSG or Cys/CySS redox in human plasma is oxidized due to sulfur amino acid intake at 0% of the RDA.
2. To determine whether steady-state GSH/GSSG or Cys/CySS becomes more reducing during dietary sulfur amino acid repletion with SAA at 3X the RDA.
3. To determine whether low or high sulfur amino acid intakes induce primary and secondary metabolic effects detectable by high-resolution 1H-NMR.

B. BACKGROUND AND SIGNIFICANCE:

Sulfur amino acids are involved in central metabolic processes. The biologically useful sulfur is derived almost exclusively from the amino acids methionine and cysteine. Methionine (Met) is an essential amino acid and is metabolized in individuals by the transulfuration pathway to form cysteine (Cys) (1). In addition to use in the primary sequence of most proteins, both Met and Cys are required for other metabolic functions. Met is converted to S-adenosylmethionine, which is used for methylation reactions (2) for structural and functional modifications of proteins, RNA and DNA, as well as synthesis of phospholipids and signaling molecules. The carbon skeleton of Met is also used for biosynthesis of polyamines, which are required for cell division and cell growth (3). Cysteine is used for biosynthesis of glutathione (GSH), coenzyme A, taurine and sulfate (4). GSH functions in redox regulation (5) and detoxification of oxidants and reactive electrophiles (6). Coenzyme A is central to fatty acid metabolism and the citric acid cycle; taurine is utilized for bile acid synthesis and osmotic regulation (7); sulfate is used as a structural component of oligosaccharides (8), transport of steroid hormones (9) and detoxification of foreign compounds (10). Thus, there is a requirement for adequate sulfur amino acid intake that extends beyond the need for adequate amounts to maintain normal protein synthesis and turnover.