Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC90LA0)

• DOT Name: Cystathionine gamma-lyase (CTH)
• Synonyms: CGL; CSE; EC 4.4.1.1; Cysteine desulfhydrase; Cysteine-protein sulfhydrase; Gamma-cystathionase; Homocysteine desulfhydrase; EC 4.4.1.2
• Gene Name: CTH
• Related Disease: Cystathioninuria
• UniProt ID: CGL_HUMAN
• PDB ID: 2NMP; 3COG; 3ELP; 5EIG; 5TSU; 5TT2; 6NBA; 6OVG
• EC Number: 4.4.1.1; 4.4.1.2
• Pfam ID: PF01053
• Sequence:
  MQEKDASSQGFLPHFQHFATQAIHVGQDPEQWTSRAVVPPISLSTTFKQGAPGQHSGFEY
  SRSGNPTRNCLEKAVAALDGAKYCLAFASGLAATVTITHLLKAGDQIICMDDVYGGTNRY
  FRQVASEFGLKISFVDCSKIKLLEAAITPETKLVWIETPTNPTQKVIDIEGCAHIVHKHG
  DIILVVDNTFMSPYFQRPLALGADISMYSATKYMNGHSDVVMGLVSVNCESLHNRLRFLQ
  NSLGAVPSPIDCYLCNRGLKTLHVRMEKHFKNGMAVAQFLESNPWVEKVIYPGLPSHPQH
  ELVKRQCTGCTGMVTFYIKGTLQHAEIFLKNLKLFTLAESLGGFESLAELPAIMTHASVL
  KNDRDVLGISDTLIRLSVGLEDEEDLLEDLDQALKAAHPPSGSHS
• Function: 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 the endogenous gaseous signaling molecule hydrogen sulfide (H2S). In vitro, it converts two L-cysteine molecules into lanthionine and H2S, also two L-homocysteine molecules to homolanthionine and H2S, which can be particularly relevant under conditions of severe hyperhomocysteinemia (which is a risk factor for cardiovascular disease, diabetes, and Alzheimer's disease). Lanthionine and homolanthionine are structural homologs of L,L-cystathionine that differ by the absence or presence of an extra methylene group, respectively. 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. By generating the gasotransmitter H2S, it participates in a number of physiological processes such as vasodilation, bone protection, and inflammation (Probable). Plays an essential role in myogenesis by contributing to the biogenesis of H2S in skeletal muscle tissue. Can also accept homoserine as substrate. Catalyzes the elimination of selenocystathionine (which can be derived from the diet) to yield selenocysteine, ammonia and 2-oxobutanoate.
• Tissue Specificity: Highly expressed in liver . Also in muscle and lower expression in most tissues except heart, pituitary gland, spleen, thymus, and vascular tissue, where it is hardly detected .
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Cysteine and methionine metabolism (hsa00270)
  Selenocompound metabolism (hsa00450)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Cysteine formation from homocysteine (R-HSA-1614603)
  Metabolism of ingested SeMet, Sec, MeSec into H2Se (R-HSA-2408508)
  Degradation of cysteine and homocysteine (R-HSA-1614558)
• BioCyc Pathway: MetaCyc:HS04050-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystathioninuria	DISOUZ3T	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Cystathionine gamma-lyase (CTH) affects the response to substance of Methotrexate.	[42]
Etoposide	DMNH3PG	Approved	Cystathionine gamma-lyase (CTH) affects the response to substance of Etoposide.	[42]
Mitoxantrone	DMM39BF	Approved	Cystathionine gamma-lyase (CTH) affects the response to substance of Mitoxantrone.	[42]

47 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cystathionine gamma-lyase (CTH).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cystathionine gamma-lyase (CTH).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cystathionine gamma-lyase (CTH).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cystathionine gamma-lyase (CTH).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cystathionine gamma-lyase (CTH).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cystathionine gamma-lyase (CTH).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cystathionine gamma-lyase (CTH).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cystathionine gamma-lyase (CTH).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cystathionine gamma-lyase (CTH).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cystathionine gamma-lyase (CTH).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Cystathionine gamma-lyase (CTH).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cystathionine gamma-lyase (CTH).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cystathionine gamma-lyase (CTH).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cystathionine gamma-lyase (CTH).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Cystathionine gamma-lyase (CTH).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Cystathionine gamma-lyase (CTH).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cystathionine gamma-lyase (CTH).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Cystathionine gamma-lyase (CTH).	[18]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cystathionine gamma-lyase (CTH).	[19]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Cystathionine gamma-lyase (CTH).	[20]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cystathionine gamma-lyase (CTH).	[11]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Cystathionine gamma-lyase (CTH).	[21]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Cystathionine gamma-lyase (CTH).	[22]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of Cystathionine gamma-lyase (CTH).	[22]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Cystathionine gamma-lyase (CTH).	[22]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Cystathionine gamma-lyase (CTH).	[23]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Cystathionine gamma-lyase (CTH).	[23]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Cystathionine gamma-lyase (CTH).	[22]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Cystathionine gamma-lyase (CTH).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cystathionine gamma-lyase (CTH).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cystathionine gamma-lyase (CTH).	[26]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Cystathionine gamma-lyase (CTH).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cystathionine gamma-lyase (CTH).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cystathionine gamma-lyase (CTH).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cystathionine gamma-lyase (CTH).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cystathionine gamma-lyase (CTH).	[31]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cystathionine gamma-lyase (CTH).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Cystathionine gamma-lyase (CTH).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cystathionine gamma-lyase (CTH).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cystathionine gamma-lyase (CTH).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cystathionine gamma-lyase (CTH).	[36]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Cystathionine gamma-lyase (CTH).	[37]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cystathionine gamma-lyase (CTH).	[38]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Cystathionine gamma-lyase (CTH).	[39]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Cystathionine gamma-lyase (CTH).	[40]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Cystathionine gamma-lyase (CTH).	[10]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Cystathionine gamma-lyase (CTH).	[41]

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