Details of Drug Off-Target (DOT)

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

• DOT Name: Methylmalonic aciduria type A protein, mitochondrial (MMAA)
• Synonyms: EC 3.6.-.-
• Gene Name: MMAA
• Related Disease:
  Methylmalonic aciduria, cblA type
  Cystic fibrosis
  Inborn error of metabolism
  Methylmalonic acidemia
  Vitamin B12-responsive methylmalonic acidemia
• UniProt ID: MMAA_HUMAN
• PDB ID: 2WWW; 8GJU
• EC Number: 3.6.-.-
• Pfam ID: PF03308
• Sequence:
  MPMLLPHPHQHFLKGLLRAPFRCYHFIFHSSTHLGSGIPCAQPFNSLGLHCTKWMLLSDG
  LKRKLCVQTTLKDHTEGLSDKEQRFVDKLYTGLIQGQRACLAEAITLVESTHSRKKELAQ
  VLLQKVLLYHREQEQSNKGKPLAFRVGLSGPPGAGKSTFIEYFGKMLTERGHKLSVLAVD
  PSSCTSGGSLLGDKTRMTELSRDMNAYIRPSPTRGTLGGVTRTTNEAILLCEGAGYDIIL
  IETVGVGQSEFAVADMVDMFVLLLPPAGGDELQGIKRGIIEMADLVAVTKSDGDLIVPAR
  RIQAEYVSALKLLRKRSQVWKPKVIRISARSGEGISEMWDKMKDFQDLMLASGELTAKRR
  KQQKVWMWNLIQESVLEHFRTHPTVREQIPLLEQKVLIGALSPGLAADFLLKAFKSRD
• Function: GTPase, binds and hydrolyzes GTP. Involved in intracellular vitamin B12 metabolism, mediates the transport of cobalamin (Cbl) into mitochondria for the final steps of adenosylcobalamin (AdoCbl) synthesis. Functions as a G-protein chaperone that assists AdoCbl cofactor delivery from MMAB to the methylmalonyl-CoA mutase (MMUT). Plays a dual role as both a protectase and a reactivase for MMUT. Protects MMUT from progressive inactivation by oxidation by decreasing the rate of the formation of the oxidized inactive cofactor hydroxocobalamin (OH2Cbl). Additionally acts a reactivase by promoting the replacement of OH2Cbl by the active cofactor AdoCbl, restoring the activity of MMUT in the presence and hydrolysis of GTP.
• Tissue Specificity: Widely expressed. Highest expression is observed in liver and skeletal muscle.
• KEGG Pathway: Cobalamin transport and metabolism (hsa04980)
• Reactome Pathway:
  Defective MUT causes MMAM (R-HSA-3359478)
  Propionyl-CoA catabolism (R-HSA-71032)
  Cobalamin (Cbl) metabolism (R-HSA-9759218)
  Defective MMAA causes MMA, cblA type (R-HSA-3359475)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methylmalonic aciduria, cblA type	DISWSXNJ	Definitive	Autosomal recessive	[1]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[2]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[3]
Methylmalonic acidemia	DISHY8VB	Strong	Genetic Variation	[4]
Vitamin B12-responsive methylmalonic acidemia	DISXEKO2	Strong	Genetic Variation	[5]

12 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 Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[19]

2 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 Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Methylmalonic aciduria type A protein, mitochondrial (MMAA).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Incidence of the cblA major subunit pilin gene amongst Burkholderia species.FEMS Microbiol Lett. 2001 Mar 1;196(1):61-6. doi: 10.1111/j.1574-6968.2001.tb10541.x.
• [3] Crystal structure and mutagenesis of the metallochaperone MeaB: insight into the causes of methylmalonic aciduria.J Biol Chem. 2007 Oct 26;282(43):31308-16. doi: 10.1074/jbc.M704850200. Epub 2007 Aug 28.
• [4] Mild clinical features of isolated methylmalonic acidemia associated with a novel variant in the MMAA gene in two Chinese siblings.BMC Med Genet. 2018 Jul 11;19(1):114. doi: 10.1186/s12881-018-0635-4.
• [5] Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia.Cell Mol Biol Lett. 2016 Jul 28;21:4. doi: 10.1186/s11658-016-0005-1. eCollection 2016.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] 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.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.