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Table 1 Biochemical pathways with metabolites changed by antipurinergic therapy in the Fragile X mouse model

From: Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1 knockout) mouse model

No.

Pathway name

Measured metabolites in the pathway (N)

Expected pathway proportion (P = N/673)

Expected hits in sample of 58 (P * 58)

Observed hits in the top 58 metabolites

Fold enrichment (Obs/Exp)

Impact (Sum VIP score)

Fraction of impact (VIP) explained (% of 136.0)

Suramin treatment effect (KO-Sur/KO-Sal)

1

Purine metabolism

41

0.061

3.54

5

1.41

27.2

20.0%

4/5 Decreased

2

Fatty acid oxidation and synthesis

39

0.057

3.37

9

2.67

16.8

12.4%

9/9 Decreased

3

Eicosanoid and resolvin metabolism

36

0.053

3.11

6

1.93

14.7

10.8%

4/6 Increased

4

Ganglioside metabolism

12

0.018

1.04

6

5.79

13.4

9.8%

6/6 Increased

5

Phospholipid metabolism

115

0.18

9.93

6

0.60

11.5

8.5%

6/6 Increased

6

Sphingolipid metabolism

72

0.105

6.21

5

0.80

11.1

8.2%

3/5 Decreased

7

Microbiome metabolism

33

0.047

2.85

3

1.05

6.7

4.9%

2/3 Decreased

8

SAM, SAH, methionine, cysteine, glutathione metabolism

22

0.032

1.90

3

1.58

6.7

4.9%

3/3 Increased

9

Vitamin B3 (Niacin, NAD+) metabolism

8

0.012

0.69

2

2.90

5.2

3.8%

1/2 Increased

10

Glycolysis and gluconeogenesis

18

0.026

1.55

2

1.29

4.2

3.1%

2/2 Decreased

11

Cholesterol, cortisol, non-gonadal steroid metabolism

29

0.042

2.50

2

0.80

3.2

2.4%

2/2 Increased

12

Nitric oxide, superoxide, peroxide metabolism

6

0.009

0.52

1

1.93

2.1

1.5%

Increased

13

Cardiolipin metabolism

12

0.018

1.04

1

0.97

2.0

1.4%

Decreased

14

Bile salt metabolism

8

0.012

0.69

1

1.45

1.8

1.3%

Increased

15

Branch chain amino acid metabolism

13

0.019

1.12

1

0.89

1.7

1.2%

Increased

16

Isoleucine, valine, threonine, or methionine metabolism

4

0.006

0.35

1

2.90

1.7

1.2%

Increased

17

Pyrimidine metabolism

31

0.051

2.68

1

0.37

1.6

1.1%

Decreased

18

Krebs cycle

17

0.025

1.47

1

0.68

1.6

1.1%

Increased

19

Vitamin B6 (pyridoxine) metabolism

5

0.007

0.43

1

2.32

1.5

1.1%

Increased

20

Pentose phosphate, gluconate metabolism

11

0.016

0.95

1

1.05

1.5

1.1%

Increased

 

20 of 60 pathways dysregulated

532 (0.79 x 673)

79% (532/673)

46 (0.79 x 58)

58

 

136.0

100%

33/58 Increased

  1. Pathways were ranked by their impact measured by summed VIP (ΣVIP; variable importance in projection) scores. A total of 58 metabolites were found to discriminate suramin-treated and saline-treated Fragile X knockout groups by multivariate partial least squares discriminant analysis (PLSDA). Significant metabolites had VIP scores of ≥1.5. Twenty (33%) of the 60 pathways interrogated had at least one metabolite with VIP scores ≥1.5. The total impact of these 58 metabolites corresponded to a summed VIP score of 136. The fractional impact of each pathway is quantified as the percent of the summed VIP score and displayed in the final column on the right in the table. Antipurinergic therapy with suramin not only corrected purine metabolism, but also produced changes in 19 other pathways associated with multi-system improvements in ASD-like symptoms.
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Molecular Autism

ISSN: 2040-2392