Could Floxies Be Dealing with an Impaired Glycine Cleavage System?

I was made aware of oxalates a few years back. Susan Owens from http://lowoxalate.info/ contacted me after she had heard I was wanting to reach out to her and learn a little more about oxalic acid and how it impairs sulfation. At first it was as if she was speaking Chinese to me. If this oxalate issue was such a big thing, why did I not know about it earlier? The day she contacted me, everything that I thought I knew about genetics changed.

Since our meeting, I went from obsessing over methylation to learning about this glyoxylate metabolic process which seemed to be impacting methionine synthase. When the glyoxylate metabolic process/glycine cleavage system is not working, the body makes endogenous oxalate, shuts down methionine synthase due to oxidative stress, starts “hogging” up the transport system it shares with sulfation, prevents D3 and carcinogenic estrogens from being sulfated and prevents us from being able to make GcMAF.

My team at MTHFR Support got to work on pulling SNPs out that were on this glyoxylate metabolic process. This is now one of the sections that most chronically ill focus on. We also started working on a section called the pentose phosphate pathway because without this pathway functioning, B6 activity is poor and the glycine cleavage system which is on the glyoxylate metabolic process has poor activity.

What is a floxie? A floxie is someone who has been injured by fluoroquinolones. Fluoroquinolones are a class of antibiotics used for an array of infections but most commonly used for urinary tract infections. When floxies are injured they usually have poor collagen production. This is where the glyoxylate metabolic process/glycine cleavage system is super important. Ascorbic acid is metabolized to oxalate at high doses and when the glyoxylate metabolic process is not working, the body makes endogenous oxalate. Proline cannot be assimilated when this metabolic process is not functioning and lysine is a big player in B6 activity itself.

What are the genes and cofactors for the glyoxylate metabolic process?

AOC1/ABP1/DAO

• Copper containing D amine oxidase
• Catalyzes the degradation of compounds such as putrescine, histamine, spermine, and spermidine, substances involved in allergic and immune responses, cell proliferation, tissue differentiation, tumor formation, and possibly apoptosis. Placental DAO is thought to play a role in the regulation of the female reproductive function.
• Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.
• Cofactor vitamin B2

AGXT

• Serine pyruvate amino transferase
• L-serine + pyruvate = 3-hydroxypyruvate + L-alanine.
• L-alanine + glyoxylate = pyruvate + glycine.
• Cofactor pyridoxal 5’-phosphate

AGXT2

• Alanine glyoxylate aminotransferase 2
• Can metabolize asymmetric dimethylarginine (ADMA) via transamination to alpha-keto-delta-(NN-dimethylguanidino) valeric acid (DMGV). ADMA is a potent inhibitor of nitric-oxide (NO) synthase, and this activity provides mechanism through which the kidney regulates blood pressure.
• L-alanine + glyoxylate = pyruvate + glycine.
• (R)-3-amino-2-methylpropanoate + pyruvate = 2-methyl-3-oxopropanoate + L-alanine.
• Cofactor pyridoxal 5’-phosphate

AGXT2L1

• Ethanolamine phosphate phospho-lyase
• Catalyzes the pyridoxal-phosphate-dependent breakdown of phosphoethanolamine, converting it to ammonia, inorganic phosphate and acetaldehyde.
• Ethanolamine phosphate + H₂O = acetaldehyde + NH₃ + phosphate.
• Cofactor pyridoxal 5’-phosphate

AMT

• Aminomethyltransferase, mitochondrial
• The glycine cleavage system catalyzes the degradation of glycine.
• [Protein]-S(8)-aminomethyldihydrolipoyllysine + tetrahydrofolate = [protein]-dihydrolipoyllysine + 5,10-methylenetetrahydrofolate + NH₃.
• Pyridoxal 5’-phosphate activity needed

BCKDHA

• 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial
• The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO₂. It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase, lipoamide acyltransferase and lipoamide dehydrogenase.
• 3-methyl-2-oxobutanoate + [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] lipoyllysine = [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] S-(2-methylpropanoyl)dihydrolipoyllysine + CO₂.
• Cofactor thiamine diphosphate

BCKDHB

• 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial
• The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO₂. It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase, lipoamide acyltransferase and lipoamide dehydrogenase.
• 3-methyl-2-oxobutanoate + [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] lipoyllysine = [dihydrolipoyllysine-residue (2-methylpropanoyl)transferase] S-(2-methylpropanoyl)dihydrolipoyllysine + CO₂.

DBT

• Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial
• The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO₂. It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acyl groups that are generated by the branched-chain alpha-keto acid decarboxylase component.
• 2-methylpropanoyl-CoA + enzyme N(6)-(dihydrolipoyl)lysine = CoA + enzyme N(6)-(S-(2-methylpropanoyl)dihydrolipoyl)lysine.
• Cofactor alpha lipoic acid

DDO

• D-aspartate oxidase
• Selectively catalyzes the oxidative deamination of D-aspartate and its N-methylated derivative, N-methyl D-aspartate.
• D-aspartate + H₂O + O₂ = oxaloacetate + NH₃ + H₂O₂.
• Cofactor riboflavin 5 phosphate

DHTKD1

• Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial
• The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO₂. It contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase
• (E2) and lipoamide dehydrogenase (E3)
• 2-oxoglutarate + [dihydrolipoyllysine-residue succinyltransferase] lipoyllysine = [dihydrolipoyllysine-residue succinyltransferase] S-succinyldihydrolipoyllysine + CO₂.
• Cofactor thiamine diphosphate

DLAT

• Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial
• The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO₂, and thereby links the glycolytic pathway to the tricarboxylic cycle.
• Cofactor alpha lipoic acid

DLD

• Dihydrolipoyl dehydrogenase, mitochondrial
• Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-chain amino acid-dehydrogenase complex). In monomeric form has additional moonlighting function as serine protease (PubMed:17404228). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction
• Protein N(6)-(dihydrolipoyl)lysine + NAD⁺ = protein N(6)-(lipoyl)lysine + NADH.
• Cofactor Riboflavin 5 phosphate

DLST

• Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial
• The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO₂. It contains multiple copies of 3 enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3).
• Succinyl-CoA + enzyme N(6)-(dihydrolipoyl)lysine = CoA + enzyme N(6)-(S-succinyldihydrolipoyl)lysine.
• Cofactor alpha lipoic acid

GLDC

• Glycine dehydrogenase (decarboxylating), mitochondrial
• The glycine cleavage system catalyzes the degradation of glycine. The P protein (GLDC) binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO₂ is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein (GCSH).
• Glycine + [glycine-cleavage complex H protein]-N(6)-lipoyl-L-lysine = [glycine-cleavage complex H protein]-S-aminomethyl-N(6)-dihydrolipoyl-L-lysine + CO₂
• Cofactor pyridoxal 5’-phosphate

GNMT

• Glycine N-methyltransferase
• Catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy). Possible crucial role in the regulation of tissue concentration of AdoMet and of metabolism of methionine.
• S-adenosyl-L-methionine + glycine = S-adenosyl-L-homocysteine + sarcosine.
• Needs B6 activity

HAO1

• Hydroxy Acid Oxidase 1
• Has 2-hydroxyacid oxidase activity. Most active on the 2-carbon substrate glycolate, but is also active on 2-hydroxy fatty acids, with high activity towards 2-hydroxy palmitate and 2-hydroxy octanoate.
• (S)-2-hydroxy acid + O₂ = 2-oxo acid + H₂O₂.
• Cofactor riboflavin 5 phosphate

HOGA1

• 4-hydroxy-2-oxoglutarate aldolase, mitochondrial
• Catalyzes the final step in the metabolic pathway of hydroxyproline.
• Needs B6 activity

LDHD

• Probable D-lactate dehydrogenase, mitochondrial
• (R)-lactate + 2 ferricytochrome c = pyruvate + 2 ferrocytochrome c + 2 H⁺.
• Cofactor riboflavin 5 phosphate

LIAS

• Sensor histidine kinase LiaS
• Member of the two-component regulatory system LiaS/LiaR probably involved in response to a subset of cell wall-active antibiotics that interfere with the lipid II cycle in the cytoplasmic membrane (bacitracin, nisin, ramoplanin and vancomycin). Seems also involved in response to cationic antimicrobial peptides and secretion stress. Activates probably LiaR by phosphorylation.
• ATP + protein L-histidine = ADP + protein N-phospho-L-histidine.
• Needs B6 activity

NDUFAB1

• Acyl carrier protein, mitochondrial
• Carrier of the growing fatty acid chain in fatty acid biosynthesis. Accessory and non-catalytic subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain
• Needs niacin

PDHX

• Pyruvate dehydrogenase protein X component, mitochondrial
• Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. This specific binding is essential for a functional PDH complex.
• Needs B6 activity

The glyoxylate metabolic process consists of B1, B2, B3, B5 (needed for CoA), B6 and alpha lipoic acid. B6 uses zinc. And B6 is lysine dependent. Lysine needs magnesium and niacin to be positively acetylated. The pentose phosphate pathway consists of magnesium and niacin as cofactors. If magnesium and niacin are deficient, the pentose phosphate pathway will function poorly and lysine will then become negatively acetylated.

Wrapping this all up, floxies should consider focusing on their B6 activity on the glyoxylate metabolic process since it is responsible for assimilating proline and needs to be functioning so poor b6 activty does not occur and the body makes endogenous oxalate where the oxalate from ascorbic acid on top of their bodies making endogenous oxalate from poor b6 activity becomes a burden by hogging up the transport system it shares with sulfation and lysine which is needed for b6 activity.