Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9Z7LHM)

• DOT Name: Macrophage metalloelastase (MMP12)
• Synonyms: MME; EC 3.4.24.65; Macrophage elastase; ME; hME; Matrix metalloproteinase-12; MMP-12
• Gene Name: MMP12
• UniProt ID: MMP12_HUMAN
• PDB ID: 1JIZ ; 1JK3 ; 1OS2 ; 1OS9 ; 1RMZ ; 1ROS ; 1UTT ; 1UTZ ; 1Y93 ; 1YCM ; 1Z3J ; 2HU6 ; 2JXY ; 2K2G ; 2K9C ; 2KRJ ; 2MLR ; 2MLS ; 2N8R ; 2OXU ; 2OXW ; 2OXZ ; 2POJ ; 2W0D ; 2WO8 ; 2WO9 ; 2WOA ; 2Z2D ; 3BA0 ; 3EHX ; 3EHY ; 3F15 ; 3F16 ; 3F17 ; 3F18 ; 3F19 ; 3F1A ; 3LIK ; 3LIL ; 3LIR ; 3LJG ; 3LK8 ; 3LKA ; 3N2U ; 3N2V ; 3NX7 ; 3RTS ; 3RTT ; 3TS4 ; 3TSK ; 3UVC ; 4EFS ; 4GQL ; 4GR0 ; 4GR3 ; 4GR8 ; 4GUY ; 4H30 ; 4H49 ; 4H76 ; 4H84 ; 4I03 ; 4IJO ; 5CXA ; 5CZM ; 5D2B ; 5D3C ; 5I0L ; 5I2Z ; 5I3M ; 5I43 ; 5I4O ; 5L79 ; 5L7F ; 5LAB ; 5N5J ; 5N5K ; 6EKN ; 6ELA ; 6ENM ; 6EOX ; 6RD0 ; 6RLY ; 7OVY ; 8B2N
• EC Number: 3.4.24.65
• Pfam ID: PF00045 ; PF00413 ; PF01471
• Sequence:
  MKFLLILLLQATASGALPLNSSTSLEKNNVLFGERYLEKFYGLEINKLPVTKMKYSGNLM
  KEKIQEMQHFLGLKVTGQLDTSTLEMMHAPRCGVPDVHHFREMPGGPVWRKHYITYRINN
  YTPDMNREDVDYAIRKAFQVWSNVTPLKFSKINTGMADILVVFARGAHGDFHAFDGKGGI
  LAHAFGPGSGIGGDAHFDEDEFWTTHSGGTNLFLTAVHEIGHSLGLGHSSDPKAVMFPTY
  KYVDINTFRLSADDIRGIQSLYGDPKENQRLPNPDNSEPALCDPNLSFDAVTTVGNKIFF
  FKDRFFWLKVSERPKTSVNLISSLWPTLPSGIEAAYEIEARNQVFLFKDDKYWLISNLRP
  EPNYPKSIHSFGFPNFVKKIDAAVFNPRFYRTYFFVDNQYWRYDERRQMMDPGYPKLITK
  NFQGIGPKIDAVFYSKNKYYYFFQGSNQFEYDFLLQRITKTLKSNSWFGC
• Function: May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.
• Tissue Specificity: Found in alveolar macrophages but not in peripheral blood monocytes.
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Macrophage metalloelastase (MMP12).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Macrophage metalloelastase (MMP12).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Macrophage metalloelastase (MMP12).	[3]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Macrophage metalloelastase (MMP12).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Macrophage metalloelastase (MMP12).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Macrophage metalloelastase (MMP12).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Macrophage metalloelastase (MMP12).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Macrophage metalloelastase (MMP12).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Macrophage metalloelastase (MMP12).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Macrophage metalloelastase (MMP12).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Macrophage metalloelastase (MMP12).	[8]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Macrophage metalloelastase (MMP12).	[9]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Macrophage metalloelastase (MMP12).	[10]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Macrophage metalloelastase (MMP12).	[8]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Macrophage metalloelastase (MMP12).	[8]
Cysteamine	DMSYFM8	Approved	Cysteamine increases the expression of Macrophage metalloelastase (MMP12).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Macrophage metalloelastase (MMP12).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Macrophage metalloelastase (MMP12).	[12]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
acrolein	DMAMCSR	Investigative	acrolein increases the secretion of Macrophage metalloelastase (MMP12).	[14]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [10] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [11] Cysteamine suppresses invasion, metastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer. PLoS One. 2012;7(4):e34437. doi: 10.1371/journal.pone.0034437. Epub 2012 Apr 20.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [14] Evaluating Mode of Action of Acrolein Toxicity in an In Vitro Human Airway Tissue Model. Toxicol Sci. 2018 Dec 1;166(2):451-464. doi: 10.1093/toxsci/kfy226.