Record Information
Version 1.0
Creation Date 2010-05-26 10:48:09 -0600
Update Date 2013-04-25 02:48:59 -0600
Accession Number T3D3774
Identification
Common Name Secalonic Acid D
Description Secalonic acid D (SAD) is a mycotoxin produced by the fungus Pencillium oxalicum, which is a common contaminant in corn and other grains. Secalonic acid D is a human teratogen that induces cleft palate. (W953)
Compound Type
  • Organic Compound
  • Mycotoxin
Chemical Structure
Thumb
Synonyms
  1. Secalonic acid D
  2. Secalonsaure D
  3. Secalonic acid D mycotoxin
  4. Ergochrome AA (2,2')-5-beta,6-alpha,10-beta-5',6'-alpha,10'-beta
  5. (7,7'-Bi-4aH-xanthene)-4a,4'a-dicarboxylic acid, 2,2',3,3',4,4',9,9'-octahydro-1,1',4,4',8,8'-hexahydroxy-3,3'-dimethyl-9,9'-dioxo-, dimethyl ester, (3S-(3-alpha,4-beta,4a-beta,7(3'R,4'S,4'aS)))
  6. SAD
Chemical Formula C32H30O14
Average Molecular Weight 638.5722
Monoisotopic Molecular Weight 638.163555668
Chemical IUPAC Name
methyl 4,8,9-trihydroxy-3-methyl-1-oxo-7-[1,5,9-trihydroxy-10a-(methoxycarbonyl)-6-methyl-8-oxo-6,7-dihydro-5H-xanthen-2-yl]-3,4-dihydro-2H-xanthene-4a-carboxylate
CAS Registry Number 35287-69-5
SMILES
COC(=O)C12OC3=C(C(O)=C(C=C3)C3=C(O)C4=C(OC5(C(O)C(C)CC(=O)C5=C4O)C(=O)OC)C=C3)C(O)=C1C(=O)CC(C)C2O
InChI Identifier
InChI=1S/C32H30O14/c1-11-9-15(33)21-25(37)19-17(45-31(21,27(11)39)29(41)43-3)7-5-13(23(19)35)14-6-8-18-20(24(14)36)26(38)22-16(34)10-12(2)28(40)32(22,46-18)30(42)44-4/h5-8,11-12,27-28,35-40H,9-10H2,1-4H3
InChI Key InChIKey=NFZJAYYORNVZNI-UHFFFAOYSA-N
Chemical Taxonomy
Kingdom Organic Compounds
Super Class Heterocyclic Compounds
Class Benzopyrans
Sub Class Xanthenes
Direct Parent Xanthenes
Alternative Parents
  • Alkyl Aryl Ethers
  • Beta Hydroxy Acids and Derivatives
  • Phenols and Derivatives
  • Cyclohexanols
  • Pyrans
  • Dicarboxylic Acids and Derivatives
  • Ketones
  • Cyclic Alcohols and Derivatives
  • Polyols
  • Carboxylic Acid Esters
  • Enols
  • Enolates
Molecular Framework Aromatic Heteropolycyclic Compounds
Substituents
  • benzene
  • dicarboxylic acid derivative
  • carboxylic acid ester
  • enolate
  • alkyl aryl ether
  • ketone
  • cyclohexanol
  • phenol derivative
  • cyclic alcohol
  • secondary alcohol
  • polyol
  • alcohol
  • hydroxy acid
  • pyran
  • enol
  • beta-hydroxy acid
External Descriptors Not Available
DrugBank ID Not Available
PubChem Compound ID 73431
KEGG ID Not Available
UniProt ID Not Available
OMIM ID Not Available
ChEBI ID Not Available
BioCyc ID Not Available
CTD ID Not Available
Stitch ID Not Available
PDB ID Not Available
ACToR ID Not Available
Wikipedia Link Not Available
Physical Properties
Appearance Not Available
Melting Point Not Available
Solubility Not Available
Predicted LogP 1.1894138046666674
Toxicity Profile
Route of Exposure Oral, dermal, inhalation, and parenteral (contaminated drugs). (W967)
Mechanism of Action Secalonic acid D (SAD) is though to induce cleft palate by causing the formation of smaller palatal shelves that fail to elevate and fuse. This inhibited palatal shelf growth is a result of the of SAD causing reduced proliferation of embryonic palatal mesenchymal (HEPM) cells. SAD binds to and phosphorylates cAMP response element binding protein (CREB), an important transcription factor required for the expression of numerous genes including proliferating cell nuclear antigen (PCNA) gene. The phosphorylation of CREB by SAD prevents it from forming the necessary transcription factor-cAMP response element complex at transcription start sites, so these genes are not expressed. This leads to reduced palatal mesenchymal cell number causing reduced palatal shelf growth and thus cleft palate. (W953, W954, W955)
Metabolism Not Available
Toxicity Values Not Available
Lethal Dose Not Available
Carcinogenicity (IARC Classification) Not Available
Uses/Sources Secalonic acid D (SAD) is a mycotoxin produced by the fungus Pencillium oxalicum, which is a common contaminant in corn and other grains. (W953)
Minimum Risk Level Not Available
Health Effects Secalonic acid D is a human teratogen that induces cleft palate. (W953)
Symptoms Cleft palate is a congenital deformity characterized by a gap on the roof of the mouth that is present at birth. (W955)
Treatment Cleft palate can be treated with corrective surgery. (W955)
References
General References
  • W953 — Dhulipala VC, Maddali KK, Welshons WV, Reddy CS. Secalonic acid D blocks embryonic palatal mesenchymal cell-cycle by altering the activity of CDK2 and the expression of p21 and cyclin E. Birth Defects Res B Dev Reprod Toxicol. 2005 Jun;74(3):233-42. [15880679 ]
  • W954 — Hanumegowda UM, Dhulipala VC, Reddy CS. Mechanism of secalonic acid D-induced inhibition of transcription factor binding to cyclic AMP response element in the developing murine palate. Toxicol Sci. 2002 Nov;70(1):55-62. [12388835 ]
  • W955 — Hanumegowda UM, Judy BM, Welshons WV, Reddy CS. Selective inhibition of murine palatal mesenchymal cell proliferation in vitro by secalonic acid D. Toxicol Sci. 2002 Mar;66(1):159-65. [11861983 ]
  • W955 — Hanumegowda UM, Judy BM, Welshons WV, Reddy CS. Selective inhibition of murine palatal mesenchymal cell proliferation in vitro by secalonic acid D. Toxicol Sci. 2002 Mar;66(1):159-65. [11861983 ]
  • W967 — Peraica M, Domijan AM. Contamination of food with mycotoxins and human health. Arh Hig Rada Toksikol. 2001 Mar;52(1):23-35. [11370295 ]

Targets

1. Cyclic AMP-responsive element-binding protein 1

Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-133 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.

Secalonic acid D (SAD) is though to induce cleft palate by causing the formation of smaller palatal shelves that fail to elevate and fuse. This inhibited palatal shelf growth is a result of the of SAD causing reduced proliferation of embryonic palatal mesenchymal (HEPM) cells. SAD binds to and phosphorylates cAMP response element binding protein (CREB), an important transcription factor required for the expression of numerous genes including proliferating cell nuclear antigen (PCNA) gene. The phosphorylation of CREB by SAD prevents it from forming the necessary transcription factor-cAMP response element complex at transcription start sites, so these genes are not expressed. This leads to reduced palatal mesenchymal cell number causing reduced palatal shelf growth and thus cleft palate. (W953, W954, W955)
UniProt ID: P16220
Gene: CREB1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:

2. Cyclic AMP-responsive element-binding protein 3

Endoplasmic reticulum (ER)-bound transcription factor that plays a role in the unfolded protein response (UPR). Involved in cell proliferation and migration, tumor suppression and inflammatory gene expression. Plays also a role in the human immunodeficiency virus type 1 (HIV-1) virus protein expression and in the herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Isoform 2 plays a role in the unfolded protein response (UPR). Isoform 2 acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration. Isoform 2 may play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HSV) core protein. Isoform 2 represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestring host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection. Isoform 3 functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Isoform 3 decreases the acetylation level of histone H4. Isoform 3 does not promote the chemotactic activity of leukocyte cells. Processed cyclic AMP-responsive element-binding protein 3: acts as a transcription factor that activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Promotes cell survival against ER stress-induced apoptotic cell death during UPR. Activates transcription from CRE and C/EBP-containing reporter genes. Induces transcriptional activation of chemokine receptors. Activates transcription of genes required for reactivation of the latent HSV-1 virus. Down-regulates Tat-dependent transcription of the HIV-1 LTR by interacting with HIV-1 Tat. It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16 and by the HCV core protein. Binds DNA to the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many viral and cellular promoters. Binds to the unfolded protein respons element (UPRE) consensus sequences sites. Binds DNA to the 5'-CCAC[GA]-3'half of ERSE II (5'-ATTGG-N-CCACG-3'). Associates with chromatin to the HERPUD1 promoter.

Secalonic acid D (SAD) is though to induce cleft palate by causing the formation of smaller palatal shelves that fail to elevate and fuse. This inhibited palatal shelf growth is a result of the of SAD causing reduced proliferation of embryonic palatal mesenchymal (HEPM) cells. SAD binds to and phosphorylates cAMP response element binding protein (CREB), an important transcription factor required for the expression of numerous genes including proliferating cell nuclear antigen (PCNA) gene. The phosphorylation of CREB by SAD prevents it from forming the necessary transcription factor-cAMP response element complex at transcription start sites, so these genes are not expressed. This leads to reduced palatal mesenchymal cell number causing reduced palatal shelf growth and thus cleft palate. (W953, W954, W955)
UniProt ID: O43889
Gene: CREB3
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:

3. Cyclic AMP-responsive element-binding protein 5

Binds to the cAMP response element and activates transcription.

Secalonic acid D (SAD) is though to induce cleft palate by causing the formation of smaller palatal shelves that fail to elevate and fuse. This inhibited palatal shelf growth is a result of the of SAD causing reduced proliferation of embryonic palatal mesenchymal (HEPM) cells. SAD binds to and phosphorylates cAMP response element binding protein (CREB), an important transcription factor required for the expression of numerous genes including proliferating cell nuclear antigen (PCNA) gene. The phosphorylation of CREB by SAD prevents it from forming the necessary transcription factor-cAMP response element complex at transcription start sites, so these genes are not expressed. This leads to reduced palatal mesenchymal cell number causing reduced palatal shelf growth and thus cleft palate. (W953, W954, W955)
UniProt ID: Q02930
Gene: CREB5
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:

4. Cyclic AMP-dependent transcription factor ATF-4

Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). It binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to ER stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA.

Secalonic acid D (SAD) is though to induce cleft palate by causing the formation of smaller palatal shelves that fail to elevate and fuse. This inhibited palatal shelf growth is a result of the of SAD causing reduced proliferation of embryonic palatal mesenchymal (HEPM) cells. SAD binds to and phosphorylates cAMP response element binding protein (CREB), an important transcription factor required for the expression of numerous genes including proliferating cell nuclear antigen (PCNA) gene. The phosphorylation of CREB by SAD prevents it from forming the necessary transcription factor-cAMP response element complex at transcription start sites, so these genes are not expressed. This leads to reduced palatal mesenchymal cell number causing reduced palatal shelf growth and thus cleft palate. (W953, W954, W955)
UniProt ID: P18848
Gene: ATF4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References: