Persulfide generated from L-cysteine inactivates tyrosine aminotransferase. Requirement for a protein with cysteine oxidase activity and gamma-cystathionase.
Liver cytosols contain factors that produce an inhibitor of tyrosine aminotransferase and other enzymes when incubated with L-cysteine or L-cystine. Cystine-dependent inactivation was caused by cystathionase and required pyridoxal 5'-phosphate, but a second protein was needed to reconstitute cysteine-dependent inactivation. A cytosolic protein was isolated that oxidized free cysteine and brought about inactivation of tyrosine aminotransferase when coincubated with cystathionase. Hematin also oxidized cysteine, which led to cysteine-dependent inactivation of tyrosine aminotransferase in the presence of cystathionase. The inactivation of tyrosine aminotransferase involved three steps: initial oxidation of cysteine to form cystine; desulfuration of cystine catalyzed by cystathionase to form the persulfide, thiocysteine; and reaction of thiocysteine (or products of its decomposition) with proteins to form protein-bound sulfane. Since dithiothreitol reactivated tyrosine aminotransferase, the sulfane probably inactivated the enzyme by oxidation of thiol groups. The present results do not indicate whether the cysteine oxidase activity is enzymatic nor do they prove which form of polysulfide inactivates tyrosine aminotransferase. Reduced glutathione greatly slowed the rates at which sulfane accumulated and at which tyrosine aminotransferase was inactivated. Incubation of DL-cystathionine with liver cytosols led to formation of cysteine, which was oxidized and cleaved to form persulfide, and caused inactivation of tyrosine aminotransferase. Thus, sulfane sulfur that is generated by an enzyme of the transulfuration pathway inactivates a transaminase by nonselective oxidation of enzyme-bound thiol groups.
D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000302:isolation & purification / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism* / Q000494:pharmacology; D050558:Cysteine Dioxygenase; D003553:Cystine / Q000378:metabolism / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D049308:Dioxygenases; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008190:Lyases / Q000378:metabolism*; D008297:Male; D010105:Oxygenases / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013440:Sulfides / Q000378:metabolism* / Q000494:pharmacology; D014444:Tyrosine Transaminase / Q000037:antagonists & inhibitors*
D013440:Sulfides; C051552:persulfides; D003553:Cystine; D010105:Oxygenases; D049308:Dioxygenases; D050558:Cysteine Dioxygenase; D014444:Tyrosine Transaminase; D008190:Lyases; D003542:Cystathionine gamma-Lyase; D003545:Cysteine