Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP9YVZI)

• DOT Name: Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (NHERF4)
• Synonyms: NHERF-4; Intestinal and kidney-enriched PDZ protein; Natrium-phosphate cotransporter IIa C-terminal-associated protein 2; Na/Pi cotransporter C-terminal-associated protein 2; NaPi-Cap2; PDZ domain-containing protein 2; PDZ domain-containing protein 3; Sodium-hydrogen exchanger regulatory factor 4
• Gene Name: NHERF4
• UniProt ID: NHRF4_HUMAN
• PDB ID: 2V90
• Pfam ID: PF00595
• Sequence:
  MVTPSPPGNHSLSLEAPRLHTASDLLGNHSLGLPLITALVGSRDRRGRVFSPVPVPLPTN
  PTTQHPTRQKLPSTLSGHRVCQAHGEPVLGLCPLLPLFCCPPHPPDPWSLERPRFCLLSK
  EEGKSFGFHLQQELGRAGHVVCRVDPGTSAQRQGLQEGDRILAVNNDVVEHEDYAVVVRR
  IRASSPRVLLTVLARHAHDVARAQLGEDAHLCPTLGPGVRPRLCHIVKDEGGFGFSVTHG
  NQGPFWLVLSTGGAAERAGVPPGARLLEVNGVSVEKFTHNQLTRKLWQSGQQVTLLVAGP
  EVEEQCRQLGLPLAAPLAEGWALPTKPRCLHLEKGPQGFGFLLREEKGLDGRPGQFLWEV
  DPGLPAKKAGMQAGDRLVAVAGESVEGLGHEETVSRIQGQGSCVSLTVVDPEADRFFSMV
  RLSPLLFLENTEAPASPRGSSSASLVETEDPSLEDTSVPSVPLGSRQCFLYPGPGGSYGF
  RLSCVASGPRLFISQVTPGGSAARAGLQVGDVILEVNGYPVGGQNDLERLQQLPEAEPPL
  CLKLAARSLRGLEAWIPPGAAEDWALASDLL
• Function: Acts as a regulatory protein that associates with GUCY2C and negatively modulates its heat-stable enterotoxin-mediated activation. Stimulates SLC9A3 activity in the presence of elevated calcium ions.
• Tissue Specificity: Expressed in kidney and the gastrointestinal tract. Not detected in brain, heart, skeletal muscle or cells of hematopoietic origin.
• Reactome Pathway: Intestinal infectious diseases (R-HSA-8942233)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (NHERF4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (NHERF4).	[3]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (NHERF4).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF4 (NHERF4).	[2]

References

• [1] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [2] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [3] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [4] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.