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Piyathida Tawornparcha

An in silico investigation of menthol metabolism

Piyathida Tawornparcha, Mahidol University

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SUPPLEMENTARY WOLFRAM MATERIALS for the ARTICLE:

Taweetham Limpanuparb, Wanutcha Lorpaiboon, Kridtin Chinsukserm (2019).
An in silico investigation of menthol metabolism. PLOS ONE 14(9): e0216577.
https://doi.org/10.1371/journal.pone.0216577
Full article PDF

An in silico investigation of menthol metabolism
by Piyathida Tawornparcha, Taweetham Limpanuparb, Wanutcha Lorpaiboon, Kridtin Chinsukserm

Introduction

There are numerous mentholated products sold in the market leading to the interests to study menthol's metabolic pathways. Available pathways from the three in vivo studies by Yamaguchi, Caldwell & Farmer (1994); Madyastha & Srivatsan (1988); Hiki et al. (2011) were in discrepancy. To tackle this problem, the in silico approach is designed by combining data from all three studies and filling in the missing links between them. The figure below shows the resulting complete pathway from this in silico approach. Note that the naming system is based on their five substitutable positions which are positions 3, 7, 8, 9 and 10.

Figure 1. Metabolic pathway of menthol in rats and human. Red, Green, and Blue numbers indicate that menthol metabolites were found in both rats and human, only in rats, and only in human respectively. Gray and Black numbers indicate menthol metabolites proposed by previous experiments and by this paper respectively. Arrows to the right and arrows upward indicate oxidation reactions +1/2

and -

respectively. Downward arrows indicate conjugation with sulfate. Dashed arrows indicate reactions of four-membered ring metabolites. Diagonal arrows toward top left indicate dehydration reaction. Main pathways are shown on the left and pathways containing glucuronide metabolites with similar possible connections are shown on the right.

1. Input preparation

The gas-phase structures were calculated at the B3LYP/6-311++G(d,p) level of theory (confirmed to be at minimum energy on the electronic potential energy surfaces by frequency calculations). The solvation energies in water of the gas-phase structures were calculated with the SMD model through single-point energy calculations. All quantum chemical calculations are done in Q-CHEM. The script for processing along with the output files for each structure can be found in supporting information of the paper itself.

2. Construction of thermodynamics table

The data on final energy, solvation energy, zero point, enthalpy and entropy for each chemical structure (menthol derivatives) are compiled into one big table.

In[]:=

Hartree=627.50947415;T=298.15;Faraday=96485.3328959;cal=4.184;RSI=8.314459848;Rlatm=0.08205733847;CWater=0.997048*1000/18.0152833;dG=RSI/cal*T*Log[Rlatm*T]/1000/HartreedGWater=RSI/cal*T*Log[CWater]/1000/Hartreeprefix=NotebookDirectory[]<>""PATH={prefix<>"common/",prefix<>"g-series/",prefix<>"o-series/",prefix<>"s-series/"};EnergyTab={};For[i=1,i≤Length[PATH],i++,filelist=Import[PATH〚i〛<>"0_file_list.txt","List"];finalenergy=Import[PATH〚i〛<>"1_final_energy.csv","CSV"];solvation=Import[PATH〚i〛<>"2_solvation.csv","CSV"];zeropoint=Import[PATH〚i〛<>"3_zero_point.csv","CSV"];enthalpy=Import[PATH〚i〛<>"4_enthalpy.csv","CSV"];entropy=Import[PATH〚i〛<>"5_entropy.csv","CSV"];tab=Table[{StringReplace[t=filelist〚j〛,{".out"""}],E0=If[(k=Position[finalenergy,t])≠{},finalenergy〚k〚1〛〚1〛〛〚2〛,0],Esolv=If[(k=Position[solvation,t])≠{},solvation〚k〚1〛〚1〛〛〚2〛,0],ZPE=If[(k=Position[zeropoint,t])≠{},zeropoint〚k〚1〛〚1〛〛〚2〛,0],H=If[(k=Position[enthalpy,t])≠{},enthalpy〚k〚1〛〚1〛〛〚2〛,0],S=If[(k=Position[entropy,t])≠{},entropy〚k〚1〛〚1〛〛〚2〛,0],Ggas=E0+H/Hartree-T*S/1000/Hartree,Gsol=Ggas+Esolv/Hartree+If[t≠"H2O.out",dG,dG+dGWater]},{j,1,Length[filelist]}];EnergyTab=Join[EnergyTab,tab];]FindC[compound_,table_]:=If[(x=Position[table,compound])≠{},{1,x〚1〛〚1〛},If[(x=Position[table,StringDrop[compound,1]])≠{},{ToExpression[StringTake[compound,1]],x〚1〛〚1〛},If[(x=Position[table,StringDrop[compound,2]])≠{},{ToExpression[StringTake[compound,2]],x〚1〛〚1〛},If[(x=Position[table,StringDrop[compound,3]])≠{},{ToExpression[StringTake[compound,3]],x〚1〛〚1〛},{compound<>"NF",1}]]]]FindGg[compound_,table_]:=(x=FindC[compound,table];x〚1〛*EnergyTab〚x〚2〛〛〚7〛)FindGs[compound_,table_]:=(x=FindC[compound,table];x〚1〛*EnergyTab〚x〚2〛〛〚8〛)EnergyTab=Join[{{"Filename","E_elec","DG_solv","ZPE","H_corr","S","G_gas","G_sol"}},EnergyTab];EnergyTab//TableFormExport[NotebookDirectory[]<>"../tables and figures/"<>"6_cmpdtab.csv",EnergyTab,"CSV"]EnergyTab=EnergyTab/.{"O4S-2""SO4-2"};

Out[]=

0.0030188

Out[]=

0.00378956

3. Reaction energy calculations

The Gibbs energies for each reaction (from the text file "list-reactions.txt") are calculated (with the correction for the standard state of liquid water ~ 55 mol/L) and associated with type, position and step of reaction in the pathway. The possible reactions are conjugation with glucuronic acid/sulfate, oxidation to alcohol, aldehyde & carboxylic acid, and formation of a four/five-membered ring. The positions can be 3,7,8,9, or 10 of the parent compound.

In[]:=

rlist=Import[NotebookDirectory[]<>"list-relative_stab.txt","List"];rlist=Import[NotebookDirectory[]<>"list-reactions.txt","List"];rlist=StringSplit[rlist," -> "];n=Length[rlist];r=StringSplit[Table[rlist〚i〛〚1〛,{i,1,n}]," + "];p=StringSplit[Table[rlist〚i〛〚2〛,{i,1,n}]," + "];rxntab=Tablerlisti1,rlisti2,Gs=

Length[p〚i〛]

∑

j=1

FindGs[p〚i〛〚j〛,EnergyTab]-

Length[r〚i〛]

∑

j=1

FindGs[r〚i〛〚j〛,EnergyTab]*Hartree,Gg=

Length[p〚i〛]

∑

j=1

FindGg[p〚i〛〚j〛,EnergyTab]-

Length[r〚i〛]

∑

j=1

FindGg[r〚i〛〚j〛,EnergyTab]*Hartree,{i,1,Length[rlist]}//TableForm

Out[]//TableForm=

C6H10O7	H2O	429778.	429755.
2H3O+ + SO4-2	3H2O	391473.	391062.
1/2O2	0O2	47165.	47164.9
0H2	H2	-737.561	-741.08
0HO2	H2O	-47980.5	-47976.2
oeeee + C6H10O7	H2O + Oeeee	3.00986	-2.90643
ooeee + C6H10O7	H2O + Ooeee	3.43277	-0.128609
ooeee + C6H10O7	H2O + oOeee	2.24605	-1.68633
oeoee + C6H10O7	H2O + Oeoee	1.21343	-3.72786
oeoee + C6H10O7	H2O + oeOee	8.29024	1.55206
oeeoe-R + C6H10O7	H2O + Oeeoe-R	4.93918	-1.55471
oeeoe-S + C6H10O7	H2O + Oeeoe-S	7.52036	-1.60503
oeeoe-R + C6H10O7	H2O + oeeOe-R	5.70956	-0.269623
oeeoe-S + C6H10O7	H2O + oeeOe-S	2.29675	-4.94903
oyeee-R + C6H10O7	H2O + Oyeee-R	2.99761	-0.285972
oyeee-S + C6H10O7	H2O + Oyeee-S	1.94309	-1.15879
oeeye-R + C6H10O7	H2O + Oeeye-R	1.22491	-7.67958
oeeye-S + C6H10O7	H2O + Oeeye-S	1.51599	-7.15639
ooeoe-R + C6H10O7	H2O + Ooeoe-R	7.88693	4.68155
ooeoe-S + C6H10O7	H2O + Ooeoe-S	10.7087	8.0602
ooeoe-R + C6H10O7	H2O + oOeoe-R	0.789135	-3.10585
ooeoe-S + C6H10O7	H2O + oOeoe-S	2.69552	-0.879266
ooeoe-R + C6H10O7	H2O + ooeOe-R	2.05475	-0.0261387
ooeoe-S + C6H10O7	H2O + ooeOe-S	1.76889	-1.54349
oxeee-R + C6H10O7	H2O + Oxeee-R	7.36446	3.92938
oxeee-S + C6H10O7	H2O + Oxeee-S	3.1335	-1.73588
oeexe-R + C6H10O7	H2O + Oeexe-R	5.75354	2.49486
oeexe-S + C6H10O7	H2O + Oeexe-S	4.93594	2.09296
oxeee-R + C6H10O7	H2O + oXeee-R	15.0423	10.3328
oxeee-S + C6H10O7	H2O + oXeee-S	15.1204	10.2469
oeexe-R + C6H10O7	H2O + oeeXe-R	9.31226	5.16388
oeexe-S + C6H10O7	H2O + oeeXe-S	9.96317	4.63088
ooeye-5A-RR + C6H10O7	H2O + oOeye-5A-RR	1.4509	-2.45728
ooeye-5A-RS + C6H10O7	H2O + oOeye-5A-RS	1.32981	-2.15117
ooeye-5A-SR + C6H10O7	H2O + oOeye-5A-SR	1.32429	-1.59589
ooeye-5A-SS + C6H10O7	H2O + oOeye-5A-SS	2.63018	-0.2546
ooeye-5A-RS + C6H10O7	H2O + ooeYe-5A-RR	7.77283	5.36265
ooeye-5A-RR + C6H10O7	H2O + ooeYe-5A-RS	7.53565	1.11657
ooeye-5A-SS + C6H10O7	H2O + ooeYe-5A-SR	2.33873	-1.11405
ooeye-5A-SR + C6H10O7	H2O + ooeYe-5A-SS	6.289	2.65181
oyeye-RR + C6H10O7	H2O + Oyeye-RR	8.2107	3.25742
oyeye-RS + C6H10O7	H2O + Oyeye-RS	2.25364	-2.01224
oyeye-SR + C6H10O7	H2O + Oyeye-SR	2.98312	0.0941376
oyeye-SS + C6H10O7	H2O + Oyeye-SS	4.32696	-4.26103
oeeyy + C6H10O7	H2O + Oeeyy	7.74225	4.00177
oeeee + 2H3O+ + SO4-2	3H2O + seeee	-24.0245	-428.923
ooeee + 2H3O+ + SO4-2	3H2O + soeee	-23.0035	-427.746
oeeoe-R + 2H3O+ + SO4-2	3H2O + seeoe-R	-19.8884	-423.488
oeeoe-S + 2H3O+ + SO4-2	3H2O + seeoe-S	-23.3741	-427.713
ooeoe-R + 2H3O+ + SO4-2	3H2O + soeoe-R	-17.4741	-422.308
ooeoe-S + 2H3O+ + SO4-2	3H2O + soeoe-S	-19.2013	-423.649
oeeee + 1/2O2	ooeee	-52.1076	-45.2904
oeeee + 1/2O2	oeoee	-56.0272	-51.4908
oeeee + 1/2O2	oeeoe-R	-51.9173	-47.1603
oeeee + 1/2O2	oeeoe-S	-50.3822	-45.729
Oeeee + 1/2O2	Ooeee	-51.6846	-42.5126
Oeeee + 1/2O2	Oeoee	-57.8237	-52.3123
Oeeee + 1/2O2	Oeeoe-R	-49.9879	-45.8085
Oeeee + 1/2O2	Oeeoe-S	-45.8717	-44.4276
ooeee + 1/2O2	oooee	-55.746	-52.2952
oeoee + 1/2O2	oooee	-51.8263	-46.0948
ooeee + 1/2O2	ooeoe-R	-50.5453	-45.8631
ooeee + 1/2O2	ooeoe-S	-49.2789	-45.0153
oeeoe-R + 1/2O2	ooeoe-R	-50.7356	-43.9933
oeeoe-S + 1/2O2	ooeoe-S	-51.0043	-44.5768
oeoee + 1/2O2	oeooe-R	-48.8314	-46.5337
oeoee + 1/2O2	oeooe-S	-48.9317	-43.2624
oeeoe-S + 1/2O2	oeooe-R	-54.4765	-52.2955
oeeoe-R + 1/2O2	oeooe-S	-53.0416	-47.5929
oeeoe-R + 1/2O2	oeeoo	-50.4565	-44.8664
oeeoe-S + 1/2O2	oeeoo	-51.9915	-46.2977
Ooeee + 1/2O2	Ooeoe-R	-46.0911	-41.0529
Ooeee + 1/2O2	Ooeoe-S	-42.003	-36.8265
Oeeoe-R + 1/2O2	Ooeoe-R	-47.7878	-37.757
Oeeoe-S + 1/2O2	Ooeoe-S	-47.816	-34.9116
oOeee + 1/2O2	oOeoe-R	-52.0022	-47.2826
oOeee + 1/2O2	oOeoe-S	-48.8295	-44.2083
oeeOe-R + 1/2O2	ooeOe-R	-54.3904	-43.7498
oeeOe-S + 1/2O2	ooeOe-S	-51.5322	-41.1712
oeoee-4D + 1/2O2	oooee-4D	-51.8746	-45.1681
oyeee-R + 1/2O2	oyoee-R	-55.7957	-51.0489
oyeee-S + 1/2O2	oyoee-S	-56.3799	-51.8338
oyeee-R + 1/2O2	oyeoe-RR	-49.5096	-45.4898
oyeee-R + 1/2O2	oyeoe-RS	-50.2891	-45.6188
oyeee-S + 1/2O2	oyeoe-SR	-49.409	-44.8598
oyeee-S + 1/2O2	oyeoe-SS	-50.1328	-44.7993
oeeye-R + 1/2O2	ooeye-R	-51.5783	-44.9231
oeeye-S + 1/2O2	ooeye-S	-51.7791	-45.0387
oeeye-S + 1/2O2	oeoye-R	-49.4857	-48.9232
oeeye-R + 1/2O2	oeoye-S	-51.0436	-48.2308
oeeye-R + 1/2O2	oeeyo-R	-49.0422	-46.6692
oeeye-S + 1/2O2	oeeyo-S	-48.6812	-45.6671
oxeee-S + 1/2O2	oxoee-S	-55.3157	-50.491
oxeee-R + 1/2O2	oxoee-R	-55.9352	-50.9884
oyeee-R + 1/2O2	oxeee-R	-73.8133	-66.7217
oyeee-S + 1/2O2	oxeee-S	-73.6357	-66.7538
oeeye-R + 1/2O2	oeexe-R	-74.3349	-70.3909
oeeye-S + 1/2O2	oeexe-S	-72.7993	-69.266
Oyeee-R + 1/2O2	Oxeee-R	-69.4465	-62.5063
Oyeee-S + 1/2O2	Oxeee-S	-72.4453	-67.3309
Oeeye-R + 1/2O2	Oeexe-R	-69.8063	-60.2165
Oeeye-S + 1/2O2	Oeexe-S	-69.3793	-60.0166
oyoee-R + 1/2O2	oxoee-R	-73.9528	-66.6612
oyoee-S + 1/2O2	oxoee-S	-72.5715	-65.411
oyoee-4D-R + 1/2O2	oxoee-4D-R	-72.9287	-66.9504
oyoee-4D-S + 1/2O2	oxoee-4D-S	-70.2177	-63.522
ooeee	oyeee-R + H2	10.1184	5.00496
ooeee	oyeee-S + H2	11.3771	5.78708
oeeoe-R	oeeye-R + H2	8.53179	5.43846
oeeoe-S	oeeye-S + H2	7.19282	4.13499
Ooeee	Oyeee-R + H2	9.68322	4.8476
Ooeee	Oyeee-S + H2	9.88742	4.7569
Oeeoe-R	Oeeye-R + H2	4.81752	-0.686411
Oeeoe-S	Oeeye-S + H2	1.18845	-1.41638
oooee	oyoee-R + H2	10.0687	6.25127
oooee	oyoee-S + H2	10.7433	6.24855
ooeoe-R	oyeoe-RR + H2	11.1541	5.37821
ooeoe-R	oyeoe-RS + H2	10.3746	5.24924
ooeoe-S	oyeoe-SR + H2	11.2471	5.94257
ooeoe-S	oyeoe-SS + H2	10.5232	6.00311
ooeoe-R	ooeye-R + H2	7.68911	4.50868
ooeoe-S	ooeye-S + H2	6.41797	3.67305
oeooe-R	oeoye-R + H2	12.1836	7.50734
oeooe-S	oeoye-S + H2	10.5298	4.80062
oeeoo	oeeyo-R + H2	9.94608	3.63565
oeeoo	oeeyo-S + H2	10.5031	4.76557
oooee-4D	oyoee-4D-R + H2	9.87534	5.07312
oooee-4D	oyoee-4D-S + H2	10.9895	6.01914
oyeoe-RR	oyeye-RR + H2	7.20574	4.29601
oyeoe-RS	oyeye-RS + H2	7.11038	4.41826
oyeoe-SR	oyeye-SR + H2	7.59109	3.82577
oyeoe-SS	oyeye-SS + H2	7.95021	4.63708
ooeye-R	oyeye-RR + H2	10.6708	5.16554
ooeye-R	oyeye-SR + H2	12.4154	6.10741
ooeye-S	oyeye-RS + H2	9.80062	5.14669
ooeye-S	oyeye-SS + H2	12.0555	6.96715
oeeyo-R	oeeyy + H2	10.5526	7.38919
oeeyo-S	oeeyy + H2	9.99559	6.25926
oeoee	oeoee-4D + H2O	15.5538	15.6422
oooee	oooee-4D + H2O	15.5055	16.569
oyoee-R	oyoee-4D-R + H2O	15.3122	15.3908
oyoee-S	oyoee-4D-S + H2O	15.7517	16.3396
oxoee-R	oxoee-4D-R + H2O	16.3362	15.1016
oxoee-S	oxoee-4D-S + H2O	18.1054	18.2285
ooeye-R	ooeye-5A-RR	3.25791	1.20091
ooeye-R	ooeye-5A-RS	4.17052	1.78892
ooeye-S	ooeye-5A-SR	2.75246	-0.378835
ooeye-S