Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNZ4N4E)

• DOT Name: Protein phosphatase Mn(2+)-dependent 1K (PPM1K)
• Synonyms: EC 3.1.3.16; Branched-chain alpha-ketoacid dehydrogenase phosphatase; BCKDH; BDP; EC 3.1.3.52; PP2C domain-containing protein phosphatase 1K; PP2C-like mitochondrial protein; PP2C-type mitochondrial phosphoprotein phosphatase; PTMP; Protein phosphatase 2C family member; Protein phosphatase 2C isoform kappa; PP2C-kappa; -phosphatase, mitochondrial
• Gene Name: PPM1K
• Related Disease:
  Non-insulin dependent diabetes
  Atrial fibrillation
  Bipolar disorder
  Cardiac failure
  Congenital heart disease
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Fatty liver disease
  Hepatocellular carcinoma
  Maple syrup urine disease
  Pneumonia
  Retinoblastoma
  Schizoaffective disorder
  Type-1/2 diabetes
  Cardiovascular disease
  leukaemia
  Leukemia
  Maple syrup urine disease, mild variant
  Nervous system disease
  Intermediate maple syrup urine disease
  Bipolar I disorder
  Psychotic disorder
  Schizophrenia
• UniProt ID: PPM1K_HUMAN
• PDB ID: 2IQ1; 4DA1; 6AK7
• EC Number: 3.1.3.16; 3.1.3.52
• Pfam ID: PF00481
• Sequence:
  MSTAALITLVRSGGNQVRRRVLLSSRLLQDDRRVTPTCHSSTSEPRCSRFDPDGSGSPAT
  WDNFGIWDNRIDEPILLPPSIKYGKPIPKISLENVGCASQIGKRKENEDRFDFAQLTDEV
  LYFAVYDGHGGPAAADFCHTHMEKCIMDLLPKEKNLETLLTLAFLEIDKAFSSHARLSAD
  ATLLTSGTTATVALLRDGIELVVASVGDSRAILCRKGKPMKLTIDHTPERKDEKERIKKC
  GGFVAWNSLGQPHVNGRLAMTRSIGDLDLKTSGVIAEPETKRIKLHHADDSFLVLTTDGI
  NFMVNSQEICDFVNQCHDPNEAAHAVTEQAIQYGTEDNSTAVVVPFGAWGKYKNSEINFS
  FSRSFASSGRWA
• Function: Serine/threonine-protein phosphatase component of macronutrients metabolism. Forms a functional kinase and phosphatase pair with BCKDK, serving as a metabolic regulatory node that coordinates branched-chain amino acids (BCAAs) with glucose and lipid metabolism via two distinct phosphoprotein targets: mitochondrial BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex and cytosolic ACLY, a lipogenic enzyme of Krebs cycle. At high levels of branched-chain ketoacids, dephosphorylates and activates mitochondrial BCKDH complex, a multisubunit complex consisting of three multimeric components each involved in different steps of BCAA catabolism: E1 composed of BCKDHA and BCKDHB, E2 core composed of DBT monomers, and E3 composed of DLD monomers. Tightly associates with the E2 component of BCKDH complex and dephosphorylates BCKDHA on Ser-337. Regulates the reversible phosphorylation of ACLY in response to changes in cellular carbohydrate abundance such as occurs during fasting to feeding metabolic transition. At fasting state, appears to dephosphorylate ACLY on Ser-455 and inactivate it. Refeeding stimulates MLXIPL/ChREBP transcription factor, leading to increased BCKDK to PPM1K expression ratio, phosphorylation and activation of ACLY that ultimately results in the generation of malonyl-CoA and oxaloacetate immediate substrates of de novo lipogenesis and gluconeogenesis, respectively. Recognizes phosphosites having SxS or RxxS motifs and strictly depends on Mn(2+) ions for the phosphatase activity. Regulates Ca(2+)-induced opening of mitochondrial transition pore and apoptotic cell death.
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congenital heart disease	DISQBA23	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Maple syrup urine disease	DIS61XRH	Strong	Genetic Variation	[8]
Pneumonia	DIS8EF3M	Strong	Genetic Variation	[2]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[9]
Schizoaffective disorder	DISLBW6B	Strong	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[10]
Cardiovascular disease	DIS2IQDX	moderate	Genetic Variation	[11]
leukaemia	DISS7D1V	moderate	Genetic Variation	[12]
Leukemia	DISNAKFL	moderate	Genetic Variation	[12]
Maple syrup urine disease, mild variant	DIS0UGU2	Moderate	Autosomal recessive	[13]
Nervous system disease	DISJ7GGT	moderate	Genetic Variation	[11]
Intermediate maple syrup urine disease	DIS5SRXS	Supportive	Autosomal recessive	[8]
Bipolar I disorder	DISD09EH	Disputed	Biomarker	[14]
Psychotic disorder	DIS4UQOT	Disputed	Genetic Variation	[14]
Schizophrenia	DISSRV2N	Limited	Biomarker	[3]

17 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 Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[20]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[21]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[22]
Tibolone	DM78XFG	Approved	Tibolone decreases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[21]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[27]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[30]

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 Protein phosphatase Mn(2+)-dependent 1K (PPM1K).	[26]

References

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