Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVDCE2H)

• DOT Name: Matrix metalloproteinase-21 (MMP21)
• Synonyms: MMP-21; EC 3.4.24.-
• Gene Name: MMP21
• Related Disease:
  Heterotaxy, visceral, 7, autosomal
  Situs inversus
• UniProt ID: MMP21_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF00045 ; PF00413 ; PF01471
• Sequence:
  MLAASIFRPTLLLCWLAAPWPTQPESLFHSRDRSDLEPSPLRQAKPIADLHAAQRFLSRY
  GWSGVWAAWGPSPEGPPETPKGAALAEAVRRFQRANALPASGELDAATLAAMNRPRCGVP
  DMRPPPPSAPPSPPGPPPRARSRRSPRAPLSLSRRGWQPRGYPDGGAAQAFSKRTLSWRL
  LGEALSSQLSVADQRRIVALAFRMWSEVTPLDFREDLAAPGAAVDIKLGFGRGRHLGCPR
  AFDGSGQEFAHAWRLGDIHFDDDEHFTPPTSDTGISLLKVAVHEIGHVLGLPHTYRTGSI
  MQPNYIPQEPAFELDWSDRKAIQKLYGSCEGSFDTAFDWIRKERNQYGEVMVRFSTYFFR
  NSWYWLYENRNNRTRYGDPIQILTGWPGIPTHNIDAFVHIWTWKRDERYFFQGNQYWRYD
  SDKDQALTEDEQGKSYPKLISEGFPGIPSPLDTAFYDRRQKLIYFFKESLVFAFDVNRNR
  VLNSYPKRITEVFPAVIPQNHPFRNIDSAYYSYAYNSIFFFKGNAYWKVVNDKDKQQNSW
  LPANGLFPKKFISEKWFDVCDVHISTLNM
• Function: Plays a specialized role in the generation of left-right asymmetry during embryogenesis. May act as a negative regulator of the NOTCH-signaling pathway. Cleaves alpha-1-antitrypsin.
• Tissue Specificity: Identified in fetal brain, kidney and liver. In adult tissues found primarily in ovary, kidney, liver, lung, placenta, brain and peripheral blood leukocytes. Expressed as well in various cancer cell lines.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Heterotaxy, visceral, 7, autosomal	DIS35W4C	Strong	Autosomal recessive	[1]
Situs inversus	DISFA7AJ	Supportive	Autosomal dominant	[2]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Matrix metalloproteinase-21 (MMP21).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Matrix metalloproteinase-21 (MMP21).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Matrix metalloproteinase-21 (MMP21).	[4]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Matrix metalloproteinase-21 (MMP21).	[4]

References

• [1] Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015 May;3(5):377-87. doi: 10.1016/S2213-2600(15)00139-3. Epub 2015 Apr 27.
• [2] A human laterality disorder caused by a homozygous deleterious mutation in MMP21. J Med Genet. 2015 Dec;52(12):840-7. doi: 10.1136/jmedgenet-2015-103336. Epub 2015 Oct 1.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] MMP-21 is expressed by macrophages and fibroblasts in vivo and in culture. Exp Dermatol. 2006 Oct;15(10):775-83. doi: 10.1111/j.1600-0625.2006.00460.x.
• [5] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.