Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ49Q27)

• DOT Name: Sarcosine dehydrogenase, mitochondrial (SARDH)
• Synonyms: SarDH; EC 1.5.8.3; BPR-2
• Gene Name: SARDH
• Related Disease:
  Renal cell carcinoma
  Type-1 diabetes
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Chronic obstructive pulmonary disease
  Clear cell renal carcinoma
  Cowden disease
  Hereditary leiomyomatosis and renal cell cancer
  High blood pressure
  Influenza
  Kidney cancer
  Lung cancer
  Lung carcinoma
  Mitochondrial disease
  Neoplasm
  Neuroblastoma
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Paraganglioma
  Pheochromocytoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal carcinoma
  Rheumatoid arthritis
  Subarachnoid hemorrhage
  Tuberculosis
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Von hippel-lindau disease
  Kidney neoplasm
  Sarcosinemia
  Hepatocellular carcinoma
  Adult glioblastoma
  Chromosomal disorder
  Colorectal carcinoma
  Glioblastoma multiforme
  Hepatitis C virus infection
  Melanoma
  Pancreatic cancer
• UniProt ID: SARDH_HUMAN
• EC Number: 1.5.8.3
• Pfam ID: PF01266 ; PF16350 ; PF01571 ; PF08669
• Sequence:
  MASLSRALRVAAAHPRQSPTRGMGPCNLSSAAGPTAEKSVPYQRTLKEGQGTSVVAQGPS
  RPLPSTANVVVIGGGSLGCQTLYHLAKLGMSGAVLLERERLTSGTTWHTAGLLWQLRPSD
  VEVELLAHTRRVVSRELEEETGLHTGWIQNGGLFIASNRQRLDEYKRLMSLGKAYGVESH
  VLSPAETKTLYPLMNVDDLYGTLYVPHDGTMDPAGTCTTLARAASARGAQVIENCPVTGI
  RVWTDDFGVRRVAGVETQHGSIQTPCVVNCAGVWASAVGRMAGVKVPLVAMHHAYVVTER
  IEGIQNMPNVRDHDASVYLRLQGDALSVGGYEANPIFWEEVSDKFAFGLFDLDWEVFTQH
  IEGAINRVPVLEKTGIKSTVCGPESFTPDHKPLMGEAPELRGFFLGCGFNSAGMMLGGGC
  GQELAHWIIHGRPEKDMHGYDIRRFHHSLTDHPRWIRERSHESYAKNYSVVFPHDEPLAG
  RNMRRDPLHEELLGQGCVFQERHGWERPGWFHPRGPAPVLEYDYYGAYGSRAHEDYAYRR
  LLADEYTFAFPPHHDTIKKECLACRGAAAVFDMSYFGKFYLVGLDARKAADWLFSADVSR
  PPGSTVYTCMLNHRGGTESDLTVSRLAPSHQASPLAPAFEGDGYYLAMGGAVAQHNWSHI
  TTVLQDQKSQCQLIDSSEDLGMISIQGPASRAILQEVLDADLSNEAFPFSTHKLLRAAGH
  LVRAMRLSFVGELGWELHIPKASCVPVYRAVMAAGAKHGLINAGYRAIDSLSIEKGYRHW
  HADLRPDDSPLEAGLAFTCKLKSPVPFLGREALEQQRAAGLRRRLVCFTMEDKVPMFGLE
  AIWRNGQVVGHVRRADFGFAIDKTIAYGYIHDPSGGPVSLDFVKSGDYALERMGVTYGAQ
  AHLKSPFDPNNKRVKGIY
• Function: Catalyzes the last step of the oxidative degradation of choline to glycine. Converts sarcosine into glycine.
• Tissue Specificity: Expressed in pancreas, liver and kidney.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Choline catabolism (R-HSA-6798163)
• BioCyc Pathway: MetaCyc:HS04663-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Renal cell carcinoma	DISQZ2X8	Definitive	Genetic Variation	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[9]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[1]
Cowden disease	DISMYKCE	Strong	Genetic Variation	[10]
Hereditary leiomyomatosis and renal cell cancer	DISN22G2	Strong	Biomarker	[11]
High blood pressure	DISY2OHH	Strong	Biomarker	[12]
Influenza	DIS3PNU3	Strong	Biomarker	[13]
Kidney cancer	DISBIPKM	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[4]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[17]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[4]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[21]
Renal carcinoma	DISER9XT	Strong	Biomarker	[14]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[22]
Subarachnoid hemorrhage	DISI7I8Y	Strong	Biomarker	[23]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[24]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[25]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[6]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[26]
Kidney neoplasm	DISBNZTN	moderate	Biomarker	[27]
Sarcosinemia	DISVUJ9N	Supportive	Autosomal recessive	[28]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[29]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[30]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[31]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[32]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[30]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[33]
Melanoma	DIS1RRCY	Limited	Biomarker	[34]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[35]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[36]
Selenium	DM25CGV	Approved	Selenium increases the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[37]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[38]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sarcosine dehydrogenase, mitochondrial (SARDH).	[43]

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 decreases the methylation of Sarcosine dehydrogenase, mitochondrial (SARDH).	[40]

References

• [1] Standardized report template for indeterminate renal masses at CT and MRI: a collaborative product of the SAR Disease-Focused Panel on Renal Cell Carcinoma.Abdom Radiol (NY). 2019 Apr;44(4):1423-1429. doi: 10.1007/s00261-018-1851-2.
• [2] Safety and Tolerability of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart (NovoLog) When Used in Insulin Pumps in Adults with Type 1 Diabetes: A Randomized, Open-Label Clinical Trial.Diabetes Technol Ther. 2020 Sep;22(9):666-673. doi: 10.1089/dia.2019.0446. Epub 2020 Jan 28.
• [3] Discovery of novel glycogen synthase kinase-3 inhibitors: Structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia.Eur J Med Chem. 2019 Jun 1;171:221-234. doi: 10.1016/j.ejmech.2019.03.039. Epub 2019 Mar 20.
• [4] Imaging Features of Succinate Dehydrogenase-deficient Pheochromocytoma-Paraganglioma Syndromes.Radiographics. 2019 Sep-Oct;39(5):1393-1410. doi: 10.1148/rg.2019180151.
• [5] Drug likeness, targets, molecular docking and ADMET studies for some indolizine derivatives.Pharmazie. 2018 Nov 1;73(11):635-642. doi: 10.1691/ph.2018.8061.
• [6] Identification and validation of suitable endogenous reference genes for gene expression studies of human bladder cancer.J Urol. 2006 May;175(5):1915-20. doi: 10.1016/S0022-5347(05)00919-5.
• [7] Pharmacological explorations of eco-friendly amide substituted (Z)--enaminones as anti-breast cancer drugs.Arch Pharm (Weinheim). 2019 Jan;352(1):e1800244. doi: 10.1002/ardp.201800244. Epub 2018 Dec 5.
• [8] Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J Med Genet. 2012 Sep;49(9):569-77. doi: 10.1136/jmedgenet-2012-101146.
• [9] IL-13-driven pulmonary emphysema leads to skeletal muscle dysfunction attenuated by endurance exercise.J Appl Physiol (1985). 2020 Jan 1;128(1):134-148. doi: 10.1152/japplphysiol.00627.2019. Epub 2019 Nov 27.
• [10] Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. 2012 Jan 15;21(2):300-10. doi: 10.1093/hmg/ddr459. Epub 2011 Oct 6.
• [11] Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet. 2018 Aug;50(8):1086-1092. doi: 10.1038/s41588-018-0170-4. Epub 2018 Jul 16.
• [12] M235-->T polymorphism of the angiotensinogen gene predicts hypertension in the elderly.J Hypertens. 1996 Sep;14(9):1061-5. doi: 10.1097/00004872-199609000-00003.
• [13] 2D-SAR, Topomer CoMFA and molecular docking studies on avian influenza neuraminidase inhibitors.Comput Struct Biotechnol J. 2018 Dec 7;17:39-48. doi: 10.1016/j.csbj.2018.11.007. eCollection 2019.
• [14] Urological cancer related to familial syndromes.Int Braz J Urol. 2017 Mar-Apr;43(2):192-201. doi: 10.1590/S1677-5538.IBJU.2016.0125.
• [15] Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.Bioorg Med Chem. 2020 Jan 1;28(1):115186. doi: 10.1016/j.bmc.2019.115186. Epub 2019 Nov 11.
• [16] Ultrastructural examination of skin biopsies may assist in diagnosing mitochondrial cytopathy when muscle biopsies yield negative results.Ann Diagn Pathol. 2017 Aug;29:41-45. doi: 10.1016/j.anndiagpath.2017.02.010. Epub 2017 Apr 28.
• [17] Paraganglioma, neuroblastoma, and a SDHB mutation: Resolution of a 30-year-old mystery.Am J Med Genet A. 2010 Jun;152A(6):1531-5. doi: 10.1002/ajmg.a.33384.
• [18] Identification of BR101549 as a lead candidate of non-TZD PPAR agonist for the treatment of type 2 diabetes: Proof-of-concept evaluation and SAR.Bioorg Med Chem Lett. 2019 Feb 15;29(4):631-637. doi: 10.1016/j.bmcl.2018.12.043. Epub 2018 Dec 19.
• [19] Synthesis, anti-proliferative activity, SAR study, and preliminary in vivo toxicity study of substituted N,N'-bis(arylmethyl)benzimidazolium salts against a panel of non-small cell lung cancer cell lines.Bioorg Med Chem. 2017 Jan 1;25(1):421-439. doi: 10.1016/j.bmc.2016.11.009. Epub 2016 Nov 5.
• [20] Update of the Standard Operating Procedure on the Use of Multiparametric Magnetic Resonance Imaging for the Diagnosis, Staging and Management of Prostate Cancer.J Urol. 2020 Apr;203(4):706-712. doi: 10.1097/JU.0000000000000617. Epub 2019 Oct 23.
• [21] The role of sarcosine metabolism in prostate cancer progression.Neoplasia. 2013 May;15(5):491-501. doi: 10.1593/neo.13314.
• [22] Synthesis and activity of substituted 4-(indazol-3-yl)phenols as pathway-selective estrogen receptor ligands useful in the treatment of rheumatoid ... J Med Chem. 2004 Dec 16;47(26):6435-8.
• [23] Aneurysmal Subarachnoid Hemorrhage with Spinal Subdural Hematoma: A Case Report and Systematic Review of the Literature.World Neurosurg. 2019 Aug;128:240-247. doi: 10.1016/j.wneu.2019.05.069. Epub 2019 May 17.
• [24] Novel Antimycobacterial Compounds Suppress NAD Biogenesis by Targeting a Unique Pocket of NaMN Adenylyltransferase.ACS Chem Biol. 2019 May 17;14(5):949-958. doi: 10.1021/acschembio.9b00124. Epub 2019 Apr 17.
• [25] Structure based docking and molecular dynamics studies: Peroxisome proliferator-activated receptors -/ dual agonists for treatment of metabolic disorders.J Biomol Struct Dyn. 2020 Feb;38(2):511-523. doi: 10.1080/07391102.2019.1581089. Epub 2019 Mar 11.
• [26] Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas.J Clin Endocrinol Metab. 2010 Mar;95(3):1274-8. doi: 10.1210/jc.2009-2170. Epub 2009 Nov 13.
• [27] Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum.J Clin Endocrinol Metab. 2015 Oct;100(10):E1386-93. doi: 10.1210/jc.2015-2689. Epub 2015 Aug 10.
• [28] Mutations in the sarcosine dehydrogenase gene in patients with sarcosinemia. Hum Genet. 2012 Nov;131(11):1805-10. doi: 10.1007/s00439-012-1207-x. Epub 2012 Jul 24.
• [29] SDHC-related deficiency of SDH complex activity promotes growth and metastasis of hepatocellular carcinoma via ROS/NFB signaling.Cancer Lett. 2019 Oct 1;461:44-55. doi: 10.1016/j.canlet.2019.07.001. Epub 2019 Jul 3.
• [30] Preliminary SAR on indole-3-carbinol and related fragments reveals a novel anticancer lead compound against resistant glioblastoma cells.Bioorg Med Chem Lett. 2017 Apr 1;27(7):1561-1565. doi: 10.1016/j.bmcl.2017.02.033. Epub 2017 Feb 17.
• [31] Construction and application of (Q)SAR models to predict chemical-induced in vitro chromosome aberrations.Regul Toxicol Pharmacol. 2018 Nov;99:274-288. doi: 10.1016/j.yrtph.2018.09.026. Epub 2018 Sep 29.
• [32] Alteration of the tumor suppressor SARDH in sporadic colorectal cancer: A functional and transcriptome profiling-based study.Mol Carcinog. 2019 Jun;58(6):957-966. doi: 10.1002/mc.22984. Epub 2019 Mar 5.
• [33] Design, synthesis, and structure-activity relationships of novel imidazo[4,5-c]pyridine derivatives as potent non-nucleoside inhibitors of hepatitis C virus NS5B.Bioorg Med Chem. 2018 May 15;26(9):2621-2631. doi: 10.1016/j.bmc.2018.04.029. Epub 2018 Apr 16.
• [34] A one-pot laccase-catalysed synthesis of coumestan derivatives and their anticancer activity.Bioorg Med Chem. 2017 Feb 1;25(3):1172-1182. doi: 10.1016/j.bmc.2016.12.025. Epub 2016 Dec 21.
• [35] 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.
• [36] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [37] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [38] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [39] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [40] 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.
• [41] 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.
• [42] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [43] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.