Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA7P0TO)

• DOT Name: N-acetylneuraminate lyase (NPL)
• Synonyms: NALase; EC 4.1.3.3; N-acetylneuraminate pyruvate-lyase; N-acetylneuraminic acid aldolase; Sialate lyase; Sialate-pyruvate lyase; Sialic acid aldolase; Sialic acid lyase
• Gene Name: NPL
• Related Disease:
  Alzheimer disease
  Atopic dermatitis
  Congestive heart failure
  Epilepsy, idiopathic generalized
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  High blood pressure
  Juvenile myoclonic epilepsy
  Schizophrenia
  Acute diarrhea
  Alcohol dependence
  Influenza
  Sensorineural hearing loss disorder
  Cholestasis
  Crohn disease
  Inflammatory bowel disease
  Prostate cancer
  Prostate carcinoma
  Psychotic disorder
  Tibial aplasia-ectrodactyly syndrome
• UniProt ID: NPL_HUMAN
• PDB ID: 6ARH
• EC Number: 4.1.3.3
• Pfam ID: PF00701
• Sequence:
  MAFPKKKLQGLVAATITPMTENGEINFSVIGQYVDYLVKEQGVKNIFVNGTTGEGLSLSV
  SERRQVAEEWVTKGKDKLDQVIIHVGALSLKESQELAQHAAEIGADGIAVIAPFFLKPWT
  KDILINFLKEVAAAAPALPFYYYHIPALTGVKIRAEELLDGILDKIPTFQGLKFSDTDLL
  DFGQCVDQNRQQQFAFLFGVDEQLLSALVMGATGAVGSTYNYLGKKTNQMLEAFEQKDFS
  LALNYQFCIQRFINFVVKLGFGVSQTKAIMTLVSGIPMGPPRLPLQKASREFTDSAEAKL
  KSLDFLSFTDLKDGNLEAGS
• Function: Catalyzes the cleavage of N-acetylneuraminic acid (sialic acid) to form pyruvate and N-acetylmannosamine via a Schiff base intermediate. It prevents sialic acids from being recycled and returning to the cell surface. Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway. Although human is not able to catalyze formation of Neu5Gc due to the inactive CMAHP enzyme, Neu5Gc is present in food and must be degraded (Probable).
• Tissue Specificity: Isoform 2 is expressed in placenta, liver, kidney, pancreas, spleen, thymus, ovary, small intestine and peripheral blood leukocyte.
• KEGG Pathway:
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sialic acid metabolism (R-HSA-4085001)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[3]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Biomarker	[4]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[6]
Juvenile myoclonic epilepsy	DISYXV1N	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[7]
Acute diarrhea	DISVH6GQ	moderate	Biomarker	[8]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[9]
Influenza	DIS3PNU3	moderate	Biomarker	[10]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Biomarker	[11]
Cholestasis	DISDJJWE	Limited	Biomarker	[12]
Crohn disease	DIS2C5Q8	Limited	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[13]
Prostate cancer	DISF190Y	Limited	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[15]
Tibial aplasia-ectrodactyly syndrome	DISN7IN9	Limited	Genetic Variation	[16]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	N-acetylneuraminate lyase (NPL) affects the response to substance of Temozolomide.	[27]
DTI-015	DMXZRW0	Approved	N-acetylneuraminate lyase (NPL) affects the response to substance of DTI-015.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of N-acetylneuraminate lyase (NPL).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N-acetylneuraminate lyase (NPL).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of N-acetylneuraminate lyase (NPL).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of N-acetylneuraminate lyase (NPL).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of N-acetylneuraminate lyase (NPL).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of N-acetylneuraminate lyase (NPL).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of N-acetylneuraminate lyase (NPL).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of N-acetylneuraminate lyase (NPL).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of N-acetylneuraminate lyase (NPL).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of N-acetylneuraminate lyase (NPL).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of N-acetylneuraminate lyase (NPL).	[24]

References

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• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
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• [21] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
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