Jenny Jones PhD and I have a hypothesis paper explaining how a MoCo Steal can lead to a Sulfite Trap involving the excess production of s-sulfocysteine (SSC), an NMDA agonist on steroids, and excess sulfite production. The MoCo Steal was a term adopted by Jenny as she liked your phrase, “NADPH steal” and felt her cascade into seizure disorder was caused by a shift of molybdenum cofactor away from SUOX towards AOX due to inadequate NAD for working ALDH enzymes as well as other blocks to this including high dose vitamin C. My daughter Zoey has MBD5 deletion which leads to increased expression of Mocosulfurase which may have caused her preferences to make more xanthine oxidase and aldehyde oxidase and less sulfite oxidase. As we continued to research, we found that the sulfite toxicity can be caused by the interaction of the immune system and hypoxia pathway, hypoxia-inducible factor 1 alpha which increases the expression of CDO to help with s-sulfenylation during oxidative stress as a mechanism by which to protect cells, but that instead of this metabolic switch ending in sulfate, individuals struggling with the MoCo Steal, end up in a Sulfite Trap.
Once someone is not working SUOX properly, there is a feed-forward mechanism because SSC’s robust effect on NMDA causes intracellular calcium overload leading to activation of calpain protease with subsequent degradation of gephyrin. Gephyrin is needed to add molybdenum to the molybdenum cofactor (MoCo).
Damaging effects of SSC due to excess calcium influx
- loss of gephyrin and ability to incorporate molybdenum into MPT
- loss of gephyrin that holds GABA receptors in place resulting in loss of functioning GABA synapses and subsequent imbalance of glutamate to GABA with effects downstream neurological effects
- inhibition of PDHC and lactic acidosis
- inhibition of glutamate aspartate transporter (GLAST) causing loss of glutamate uptake in neurons resulting in low brain energy levels
- potassium and sodium wasting via over-excitation of NMDA in the kidneys with subsequent loss of the ability to uptake bicarbonate, increased H+ ions, and retention of chloride causing a non-anion gap hyperchloremic acidosis
Sulfites direct damaging effects include:
- need for metabolizing by cytochrome C using oxygen leading to loss of mitochondrial oxygen and production of sulfite radicals. The oxidative stress triggers HIF-1alpha which increases CDO and leads to more sulfite due to the loss of SUOX activity
- inhibition of ALDH7A1 with subsequent altered lysine metabolism resulting in a build-up of P6C and functional B6 deficiency
- cleavage of the methylene bridge of thiamine causing thiamine deficiency
- binding to B12 as sulfito-cobalamin causing a functional B12 deficiency and loss of MUT causing inadequate succinyl CoA and slowed heme synthesis
- inhibiting glutamate dehydrogenase in neurons results in decreased alpha-ketoglutarate, diminished movement of the TCA cycle, decreased mitochondrial membrane potential, and decreased ATP synthesis.
- inhibiting glutamate dehydrogenase in other cells leads to similar effects, but also loss of alpha-ketoglutarate to act as an antioxidant during oxidative stress
- damage to lysosomes causing them to leak cyanide which ties up MPST in the production of thiocyanate. Thiocyanate causes loss of uptake of iodine into the thyroid gland and hypothyroidism
Functional B6 deficiency from ALDH7A1 inhibition causes:
- inability to complete de novo NAD production via the kynurenine pathway
- loss of CBS and CSE activity
- inability to start heme synthesis due to ALAS requires B6 (or minimal ability due to triage flux of B6 towards important cellular needs)
- decreased serine hydroxy methyltransferase (SHMT) activity leading to decreased glycine production from serine, but glycine supplements cause reactions due to acting as co-agonists to NMDA
- severe cases lead to a lack of histamine production (resolution of histamine intolerance but at the same time severe neurological presentation with loss of motor coordination)
- less severe cases, decreased ability to metabolize histamine with ALDH7A1 side of histamine metabolism leading to increased burden on HNMT
- decreased glutamate to GABA conversion
Sulfite binds to cystine to make SSC which can cause cystine deficiency. This could be restored by SSC being taken up by cells and metabolized using glutathione, but the shift towards the hypoxia pathway causes more cysteine to be shuttled towards CDO and overall there is a glutathione deficiency. Due to oxidative stress, cysteine is also shuttled towards CDO to produce cysteine sulfenic acid to protect enzymes during oxidative stress so that when it resolves the cell can resume function.
Cysteine deficiency then causes…
- loss of lipoic acid, CoA, and FAD (FAD synthase requires molybdopterin which is made with GTP and cysteine)
- loss of NRF2 activation leading to low expression of antioxidant genes
- loss of NRF2 activation leading to keratinization
- vitiligo due to failure to prevent apoptosis of melanocytes
- (CoQ10 needs cysteine for production – prenylation- but this seems conserved due to needing large amounts of ubiquinol for degradation of HIF-1apha)