Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX0TT3W)

• DOT Name: Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC)
• Synonyms: Alkylcobalamin:glutathione S-alkyltransferase; EC 2.5.1.151; CblC; Cyanocobalamin reductase (cyanide-eliminating); EC 1.16.1.6; Methylmalonic aciduria and homocystinuria type C protein; MMACHC
• Gene Name: MMACHC
• Related Disease:
  Methylmalonic aciduria and homocystinuria type cblC
  Homocystinuria
  Hypogonadism
  Pulmonary arterial hypertension
  Vitamin B12 deficiency
  Dilated cardiomyopathy 1A
  Megaloblastic anemia
  Methylmalonic acidemia
  Movement disorder
  Classic phenylketonuria
  Glycogen storage disease VI
  Hemolytic-uremic syndrome
  Phenylketonuria
• UniProt ID: MMAC_HUMAN
• PDB ID: 3SBY; 3SBZ; 3SC0; 3SOM; 5UOS; 7WUZ
• EC Number: 1.16.1.6; 2.5.1.151
• Pfam ID: PF16690
• Sequence:
  MEPKVAELKQKIEDTLCPFGFEVYPFQVAWYNELLPPAFHLPLPGPTLAFLVLSTPAMFD
  RALKPFLQSCHLRMLTDPVDQCVAYHLGRVRESLPELQIEIIADYEVHPNRRPKILAQTA
  AHVAGAAYYYQRQDVEADPWGNQRISGVCIHPRFGGWFAIRGVVLLPGIEVPDLPPRKPH
  DCVPTRADRIALLEGFNFHWRDWTYRDAVTPQERYSEEQKAYFSTPPAQRLALLGLAQPS
  EKPSSPSPDLPFTTPAPKKPGNPSRARSWLSPRVSPPASPGP
• Function: Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate. Cyanocobalamin constitutes the inactive form of vitamin B12 introduced from the diet, and is converted into the active cofactors methylcobalamin (MeCbl) involved in methionine biosynthesis, and 5'-deoxyadenosylcobalamin (AdoCbl) involved in the TCA cycle. Forms a complex with the lysosomal transporter ABCD4 and its chaperone LMBRD1, to transport cobalamin across the lysosomal membrane into the cytosol. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR (methionine synthase) which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine. Also acts as a glutathione transferase by catalyzing the dealkylation of the alkylcob(III)alamins MeCbl and AdoCbl, using the thiolate of glutathione for nucleophilic displacement to generate cob(I)alamin and the corresponding glutathione thioether. The conversion of incoming MeCbl or AdoCbl into a common intermediate cob(I)alamin is necessary to meet the cellular needs for both cofactors. Cysteine and homocysteine cannot substitute for glutathione in this reaction.
• Tissue Specificity: Widely expressed. Expressed at higher level in fetal liver. Also expressed in spleen, lymph node, thymus and bone marrow. Weakly or not expressed in peripheral blood leukocytes.
• KEGG Pathway:
  Vitamin digestion and absorption (hsa04977)
  Cobalamin transport and metabolism (hsa04980)
• Reactome Pathway:
  Defective MMACHC causes MAHCC (R-HSA-3359474)
  Cobalamin (Cbl) metabolism (R-HSA-9759218)
  Defective MMADHC causes MMAHCD (R-HSA-3359473)
• BioCyc Pathway: MetaCyc:ENSG00000132763-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methylmalonic aciduria and homocystinuria type cblC	DISUDX17	Definitive	Autosomal recessive	[1]
Homocystinuria	DISK3N1S	Strong	Genetic Variation	[2]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[3]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Genetic Variation	[4]
Vitamin B12 deficiency	DIS91UJ1	Strong	Genetic Variation	[5]
Dilated cardiomyopathy 1A	DIS0RK9Z	moderate	Biomarker	[6]
Megaloblastic anemia	DISVIZPC	moderate	Genetic Variation	[7]
Methylmalonic acidemia	DISHY8VB	moderate	Genetic Variation	[2]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[3]
Classic phenylketonuria	DISLU64N	Limited	Genetic Variation	[8]
Glycogen storage disease VI	DIS46FMA	Limited	Genetic Variation	[9]
Hemolytic-uremic syndrome	DISSCBGW	Limited	Genetic Variation	[10]
Phenylketonuria	DISCU56J	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cyanocobalamin reductase / alkylcobalamin dealkylase (MMACHC).	[19]

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] Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria.BMC Med Genet. 2018 Aug 29;19(1):154. doi: 10.1186/s12881-018-0666-x.
• [3] MMACHC gene mutation in familial hypogonadism with neurological symptoms.Gene. 2015 Dec 15;574(2):380-4. doi: 10.1016/j.gene.2015.08.029. Epub 2015 Aug 14.
• [4] Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene.Eur J Pediatr. 2014 Dec;173(12):1707-10. doi: 10.1007/s00431-014-2330-6. Epub 2014 May 24.
• [5] HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain.Hum Mol Genet. 2015 Jun 15;24(12):3335-47. doi: 10.1093/hmg/ddv083. Epub 2015 Mar 3.
• [6] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [7] Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia.Hum Mol Genet. 2013 Nov 15;22(22):4591-601. doi: 10.1093/hmg/ddt308. Epub 2013 Jul 3.
• [8] Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population.Front Genet. 2018 Apr 20;9:122. doi: 10.3389/fgene.2018.00122. eCollection 2018.
• [9] First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type.Brain Dev. 2015 Mar;37(3):286-91. doi: 10.1016/j.braindev.2014.06.007. Epub 2014 Jun 25.
• [10] Do not Miss Rare and Treatable Cause of Early-Onset Hemolytic Uremic Syndrome: Cobalamin C Deficiency.Nephron. 2019;142(3):258-263. doi: 10.1159/000497822. Epub 2019 May 28.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [19] 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.