Anew pathway of histidine metabolism initiated by the adduction of glutathione to urocanic acid

In the first step of i.-histidine catabolism, urocanatc is formed by the action of histidinc ammonia-lyasc. In liver, urocanatc is metabolized by urocanatc hydratasc to 4-imidazolonc-5-propionatc. In epidermis, however, histidinc metabolism terminates with the formation of urocanatc, since urocanate hydratasc is absent from ihe skin. On the other hand, we found that histidinc is metabolized in part through an alternative pathway. In the first step of this pathway, 5-|2-carboxy-l-{l//-imidazol-4-yl)ethyl|glutathione [GS(CIE)|, an adduct of urocanatc and glutathionc. is formed. GS(CIE) is catabolizcd to ('ys(CIE)-Gly and then to Cys(ClE) just like the metabolism of glutathionc. Cys(CIE) is "further metabolized lo /VAc-Cys(CIE). CIE-3-mcrcaptolactate also is formed from ('ys(CIE) via an intermediate CIE-3-mercaptopyruvatc. These metabolites were isolated from normal human urine. CIE-2-mercaptnacetatc also was isolated from the urine, and its precursor is postulated to be CIE-2-mcrcaptoacctaldehyde. The /V-acetylating enzyme acting upon the formation of /VAc-Cys(CIE) recognizes the stcrcoisomcrism of asymmetric carbon atoms on Cys(CIE) molecule, while no recognition of stcreoisomcrism occurs in enzymatic degradation of GS(C'IE) to Cys(CIE) through a formation of Cys(CIE)-Gly. The formation of Cys(CIE) may participate in part in the accumulation and the elimination of the epidermal urocanatc under conditions of sunlight irradiation.