Catalyzes the last step in the trans-sulfuration pathway from L-methionine to L-cysteine in a pyridoxal-5'-phosphate (PLP)-dependent manner, which consists on cleaving the L,L-cystathionine molecule into L-cysteine, ammonia and 2-oxobutanoate. Part of the L-cysteine derived from the trans-sulfuration pathway is utilized for biosynthesis of the ubiquitous antioxidant glutathione. Besides its role in the conversion of L-cystathionine into L-cysteine, it utilizes L-cysteine and L-homocysteine as substrates (at much lower rates than L,L-cystathionine) to produce hydrogen sulfide (H2S). In vitro, it converts two L-cysteine molecules into lanthionine and H2S, and two L-homocysteine molecules to homolanthionine and H2S, which can be particularly relevant under conditions of severe hyperhomocysteinemia. Lanthionine and homolanthionine are structural homologs of L,L-cystathionine that differ by the absence or presence of an extra methylene group, respectively (By similarity). Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function (PubMed:19903941, PubMed:22244329). By generating the gasotransmitter H2S, it participates in a number of physiological processes such as vasodilation, bone protection, and inflammation (PubMed:18948540) (By similarity). Plays an essential role in myogenesis by contributing to the biogenesis of H2S in skeletal muscle tissue (PubMed:33826201). Can also accept homoserine as substrate (By similarity). Catalyzes the elimination of selenocystathionine (which can be derived from the diet) to yield selenocysteine, ammonia and 2-oxobutanoate (By similarity). H2O + L,L-cystathionine = 2-oxobutanoate + L-cysteine + NH4(+) H2O + L-cysteine = H(+) + hydrogen sulfide + NH4(+) + pyruvate H2O + L-homocysteine = 2-oxobutanoate + H(+) + hydrogen sulfide + NH4(+) L-homoserine = 2-oxobutanoate + NH4(+) H2O + L-selenocystathionine = 2-oxobutanoate + L-selenocysteine + NH4(+) Activated by calmodulin in the presence of calcium ions. Amino-acid biosynthesis; L-cysteine biosynthesis; L-cysteine from L-homocysteine and L-serine: step 2/2. Homotetramer (By similarity). Interacts with CALM in a calcium-dependent manner (PubMed:18948540). Detected in liver and kidney, and at lower levels in small intestine (at protein level) (PubMed:15038791). Highly expressed in liver, kidney and lung, detected at lower levels in stomach, small intestine and adipose tissue, and hardly found in heart, bone, and thymus (PubMed:15038791, PubMed:20305127). First detected at low levels in embryonic liver after 12.5 days of embryonic development. Highly expressed in liver and kidney after 18.5 days of embryonic development. Expressed at high levels in liver and kidney after birth and in adults. Age-dependent expression in mouse skeletal muscles; protein expression in skeletal muscles increased 5 days after birth, and remained stable until 10 weeks, then slightly decreased at 26 weeks and was significantly lower at 51 weeks (PubMed:33826201). Tumor necrosis factor alpha (TNF-alpha) promotes the binding of SP1 to the CSE promoter, inducing its transcription. No visible phenotype at birth. Mice exhibit strongly decreased levels of hydrogen sulfide (H2S) in heart and aorta. Mice also show absence of protein sulfhydration on target proteins. Hydrogen sulfide serum levels are also lower than normal. No effect on brain hydrogen sulfide levels. Age-dependent hypertension beginning at about seven weeks of age (PubMed:18948540, PubMed:19903941). Deteriorated the loss of skeletal muscle mass in aging mice (PubMed:33826201). Belongs to the trans-sulfuration enzymes family.