Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5X1G9Q)

• DOT Name: Mitochondrial-processing peptidase subunit alpha (PMPCA)
• Synonyms: Alpha-MPP; Inactive zinc metalloprotease alpha; P-55
• Gene Name: PMPCA
• Related Disease:
  Mitochondrial disease
  Spinocerebellar ataxia type 1
  Adenoma
  Arteriosclerosis
  Atherosclerosis
  Autosomal recessive spinocerebellar ataxia 2
  Cerebellar ataxia
  Hepatocellular carcinoma
  Medullary thyroid gland carcinoma
  Neoplasm
  Pheochromocytoma
  Primary aldosteronism
  Prostate adenocarcinoma
  Tuberculosis
  Movement disorder
  Epilepsy
  Nervous system disease
  Type-1 diabetes
  Adrenal adenoma
  Adrenocortical carcinoma
  Hepatitis C virus infection
  Retinitis pigmentosa 1
  Spinocerebellar ataxia
• UniProt ID: MPPA_HUMAN
• Pfam ID: PF00675 ; PF05193
• Sequence:
  MAAVVLAATRLLRGSGSWGCSRLRFGPPAYRRFSSGGAYPNIPLSSPLPGVPKPVFATVD
  GQEKFETKVTTLDNGLRVASQNKFGQFCTVGILINSGSRYEAKYLSGIAHFLEKLAFSST
  ARFDSKDEILLTLEKHGGICDCQTSRDTTMYAVSADSKGLDTVVALLADVVLQPRLTDEE
  VEMTRMAVQFELEDLNLRPDPEPLLTEMIHEAAYRENTVGLHRFCPTENVAKINREVLHS
  YLRNYYTPDRMVLAGVGVEHEHLVDCARKYLLGVQPAWGSAEAVDIDRSVAQYTGGIAKL
  ERDMSNVSLGPTPIPELTHIMVGLESCSFLEEDFIPFAVLNMMMGGGGSFSAGGPGKGMF
  SRLYLNVLNRHHWMYNATSYHHSYEDTGLLCIHASADPRQVREMVEIITKEFILMGGTVD
  TVELERAKTQLTSMLMMNLESRPVIFEDVGRQVLATRSRKLPHELCTLIRNVKPEDVKRV
  ASKMLRGKPAVAALGDLTDLPTYEHIQTALSSKDGRLPRTYRLFR
• Function: Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
• Tissue Specificity: Ubiquitously expressed with highest expression in fetal tissues and adult brain, cerebellum and cerebellar vermis.
• Reactome Pathway:
  Processing of SMDT1 (R-HSA-8949664)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Spinocerebellar ataxia type 1	DISF7BO2	Definitive	Genetic Variation	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Autosomal recessive spinocerebellar ataxia 2	DISEYHEV	Strong	Autosomal recessive	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[6]
Primary aldosteronism	DISOEFNH	Strong	Altered Expression	[3]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[7]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[8]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[9]
Epilepsy	DISBB28L	Disputed	Genetic Variation	[10]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[10]
Type-1 diabetes	DIS7HLUB	Disputed	Genetic Variation	[10]
Adrenal adenoma	DISC2UN8	Limited	Altered Expression	[11]
Adrenocortical carcinoma	DISZF4HX	Limited	Altered Expression	[11]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[12]
Retinitis pigmentosa 1	DISSLQPP	Limited	Genetic Variation	[13]
Spinocerebellar ataxia	DISYMHUK	Limited	Genetic Variation	[13]

3 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 Mitochondrial-processing peptidase subunit alpha (PMPCA).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[21]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[22]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mitochondrial-processing peptidase subunit alpha (PMPCA).	[25]

References

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• [2] Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3.Brain. 1996 Oct;119 ( Pt 5):1497-505. doi: 10.1093/brain/119.5.1497.
• [3] Evidence for a potential role for HDL as an important source of cholesterol in human adrenocortical tumors via the CLA-1 pathway.Endocr J. 1999 Feb;46(1):27-34. doi: 10.1507/endocrj.46.27.
• [4] Identification of novel human high-density lipoprotein receptor Up-regulators using a cell-based high-throughput screening assay.J Biomol Screen. 2007 Mar;12(2):211-9. doi: 10.1177/1087057106297568. Epub 2007 Jan 26.
• [5] PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia. Brain. 2015 Jun;138(Pt 6):1505-17. doi: 10.1093/brain/awv057. Epub 2015 Mar 25.
• [6] The RET C611Y mutation causes MEN 2A and associated cutaneous.Endocr Connect. 2018 Sep 1;7(9):998-1005. doi: 10.1530/EC-18-0220.
• [7] Modeling African American prostate adenocarcinoma by inducing defined genetic alterations in organoids.Oncotarget. 2017 Apr 19;8(31):51264-51276. doi: 10.18632/oncotarget.17230. eCollection 2017 Aug 1.
• [8] A Nanostructured Lipid System to Improve the Oral Bioavailability of Ruthenium(II) Complexes for the Treatment of Infections Caused by Mycobacterium tuberculosis.Front Microbiol. 2018 Dec 6;9:2930. doi: 10.3389/fmicb.2018.02930. eCollection 2018.
• [9] Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA.Brain. 2016 Mar;139(Pt 3):e19. doi: 10.1093/brain/awv362. Epub 2015 Dec 10.
• [10] Neurologic disorders associated with anti-glutamic acid decarboxylase antibodies: A comparison of anti-GAD antibody titers and time-dependent changes between neurologic disease and type I diabetes mellitus.J Neuroimmunol. 2018 Apr 15;317:84-89. doi: 10.1016/j.jneuroim.2018.01.007. Epub 2018 Jan 9.
• [11] Ribonucleic acid expression of the CLA-1 gene, a human homolog to mouse high density lipoprotein receptor SR-BI, in human adrenal tumors and cultured adrenal cells.J Clin Endocrinol Metab. 1997 Aug;82(8):2522-7. doi: 10.1210/jcem.82.8.4123.
• [12] Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice.J Hepatol. 2012 Jul;57(1):17-23. doi: 10.1016/j.jhep.2012.02.018. Epub 2012 Mar 10.
• [13] Autosomal-dominant cerebellar ataxia with retinal degeneration (ADCA type II) is genetically different from ADCA type I.Ann Neurol. 1994 Apr;35(4):439-44. doi: 10.1002/ana.410350411.
• [14] 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.
• [15] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [16] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [17] 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.
• [18] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.