Does migraine medicine Topiramate work by supplanting Pyridoxal phosphate in enzymes?

Question

I have seen it said that the precise mechanism of action of migraine medicine Topiramate is not known. But I certainly see a resemblance between that molecule and PLP (Pyridoxal phosphate, the activated form of vitamin B6).

A significant similarity is that both have an "offshoot chain" (Topiramate's sulfamate taking the place of PLP's phosphate) where PLP's phosphate is what binds it to enzymes in the first place, and both have a more electronegative element in the middle of what would otherwise be a six-carbon ring, apparently important in the typical PLP enzyme reaction.

I have been wondering if Topiramate supplants PLP in the enzyme glutamate decarboxylase, changing the reaction into a deamination. This would deplete glutamate, causing the pill's migraine relief, and the deamination could even cause Topiramate hyperammonemia.

If it does the same or similar to serine hydroxymethyltransferase, which is also PLP dependent, it could cause glycine deficiency, thus collagen deficiency - and this would even explain Topiramate hair loss.

When you look at it this way, it's frankly hard to imagine the mechanism of action is anything different. Have I stumbled upon it? Or has this been suggested already?

Answer 1

Background

Topiramate (TPM) is an anticonvulsive and antimigraine drug that helps prevent or reduce the frequency of epileptic seizures and that is used as a prophylaxis of migraine. (Shank and Maryanoff, 2008)

TPM not only inhibits kainate subtypes and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtypes of glutamate activated ionotrophic receptors, the modulatory effects on GABA_A receptors and voltage-gated Ca²⁺ and Na⁺ channels (Gibbs et al., 2000), but also inhibits carbonic anhydrase enzymes (demonstrated in electrophysiologic and biochemical studies). see drugs.com

OP question

It is an intriguing possible correlation that “Topiramate supplants PLP in the enzyme glutamate decarboxylase [GAD]”, notably based on structural similarity of the alkyl-sulfamate to the alkyl-phosphate as well as the linked rings.

However, the literature does not seem to align with this premise:

1. Shank and Maryanoff et al.(2008) noted that “[Topiramate’s] sulfamate moiety is essential, but not sufficient, for its pharmacodynamic properties.”
   
2. Whereas PLP is a substitute pyridine (planar) derivative, TPM is a sulfamate, substituted derivative of β-D-fructopyranose (Maryanoff et al., 1987) where its substituted ring is in the boat conformation and its ring is puckered. See the crystal structure as entry SEQKAA02 at CCDC
   

3. TPM does not seem to inhibit glutamate decarboxylase. “Single-dose and repeated treatments with TPM were without effect on the activities of GABA-T and GAD (Fig. 2) in mouse brain at 4 h after administration.” (Sills et al., 2000)
   
4. GAD inhibition and Topiramate treatment have opposite effects. “Clinical evidence shows that lowered GAD activity is associated with several forms of epilepsy which are often treatment resistant.” (Zhang et al. 2017; Lloyd et al. 1986) Furthermore, Zhang et al. synthesized an ethyl ketopentenoate (EKP), a lipid-permeable GAD-inhibitor, and used it to induce refractory seizures in zebrafish larvae. (yes, that’s mean.. but informative here.)
   
   

Molecular basis of carbonic anhydrase inhibition

Topiramate is a carbonic anhydrase inhibitor (multiple classes), a Zn-dependent metalloenzyme. Below is how Topiramate (green) binds to human carbonic anhydrase II. The zinc ion is shown as a silver sphere. RCSB entry 3HKU.pdb DOI: 10.2210/pdb3HKU/pdb and Lopez et al. (2009):

Conclusion

Given the above, I wouldn’t think the apparent structural similarity of Topiramate to PLP is relevant to epilepsy and/or migraine treatment.

References

Lloyd, KG, Bossi, L, Morselli, PL, Munari, C, Rougier, M and Loiseau, H (1986) “Alterations of GABA-mediated synaptic transmission in human epilepsy” Adv. Neurol. 44:1033–1044. source

Lopez, M, Paul, B, Hofmann, A, Morizzi, J, Wu, QC, Charman, SA, Innocenti, A, Vullo, D, Supuran, CT and Poulsen, SA (2009) “S-Glycosyl Primary Sulfonamides−A New Structural Class for Selective Inhibition of Cancer-Associated Carbonic Anhydrases” J. Med. Chem. 52:6421-6432. DOI: 10.1021/jm900914e

Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP (1987) “Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate and related compounds” J. Med. Chem. 30:880–887. DOI: 10.1021/jm00388a023

Shank, RP and Maryanoff, BE (2008) “Molecular pharmacodynamics, clinical therapeutics, and pharmacokinetics of topiramate” CNS Neurosci. Ther. 14:120-142. DOI: 10.1111/j.1527-3458.2008.00041.x

Sills, GJ, Leach, JP, Kilpatrick, WS, Fraser, CM and Brodie, MJ (2000) “Concentration-Effect Studies with Topiramate on Selected Enzymes and Intermediates of the GABA Shunt” Epilepsia 41 (Suppl. 1):S30-S34. DOI: 10.1111/j.1528-1157.2000.tb02168.x