torsdag den 14. marts 2019

Fatty acid oxidation, CPS1 and urea cycle in ME

When beta-oxidation of fatty acids is blocked, there is an increase in omega-oxidation, which produces dicarboxylic acids (adipic, suberic and sebacic acid). Elevated levels in plasma or urine of dicarboxylic acids are indicative of dysregulated fatty acid oxidation. Inadequate level of carnitine can lead to elevated levels of dicarboxylic acids. This is fx. observed in enteric dysfunction (1),

Some ME patients have changed plasma levels in different studies compared to normal controls of the following metabolites:
  • increased sebacic acid and pristanic acid (2)
  • increased adipoylcarnitine (3, 4), and increased methyladipoylcarnitine (3)
  • decreased carnitine (5)
3- methyladipic acid is formed upon omega-oxidation of phytanic acid. Pristanic acid is formed of phytanic acid (6).

In certain long-chain fatty acid oxidation defects, fatty acylation of an active site residue of carbamoylphosphate synthetase 1 (CPS1) directly affects the urea cycle detoxification capacity (7).

In valproic acid induced toxicity CPS1 may be inhibited of omega-oxidation metabolites (8).

Some ME patients have dysregulated urea cycle (9).

Yamano et al hypothesized that the increase in the ratio ornithine / citrulline in plasma from ME patients may reflect either CPS1 or ornithine transcarbamoylase (OCT) dysfunction (10).

In OTC deficiency carbamoyl phosphate cannot replenish the urea cycle. The carbamoyl phosphate instead goes into the uridine monophosphate (UMP)- synthetic pathway. This means that orotic acid levels in the blood will increase. I have not found increased levels of orotate in any of the ME metabolism studies.

N-acetylglutamic acid is an essential cofactor for activation of  CPS1. Some ME patients have increased N-acetylglutamic acid plasma level, thus the cofactor is present (3).

Is CPS1 activated or not in ME? Are omega-oxidation metabolites involved?

SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle

SIRT5 deacetylates CPS1 and upregulates its activity. During fasting, NAD in liver mitochondria increases, thereby triggering SIRT5 deacetylation of CPS1 and adaptation to the increase in amino acid catabolism (11). 

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Figure from Takashi Nakagawa and Leonard Guarente, AGING, June 2009, Vol. 1 No. 6 ref 12. 

Is a dysregulated NAD/NADH ratio involved in CPS1 dysfunction in ME?

Glycine and CPS1

Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle.

Higher CPS1 expression is associated with less glycine in the blood, and vice versa.

Glycine is a major biochemical mechanism to eliminate ammonia. Glycine conjugating with benzoic acid leads to hippuric acid, which is abundantly found in urine samples.

Variations in CPS1 quantity and thus the glycine pool may also influence one-carbon metabolism and the bioavailability of betaine (13).

Is glycine used to eliminate ammonia in ME patients?

Another route of excretion of excess nitrogen

Phenylacetylglutamine and 4-hydroxyphenyl acetylglutamine provide another route of excretion of excess nitrogen from the body. Phenylacetate in the blood (some from the host and some from gut fermentation) conjugates with glutamine to phenylacetylglutamine, which is excreted in the urine (1).

4-hydroxyphenylacetate is derived from fermentation af tyrosine by the gut microbiome (1).

Children with enteric dysfunction had elevated serum levels of phenylacetate, 4-hydroxyphenylacetate and phenylacetylglutamine (1).

4-hydroxyphenylacetate and derivates were increased in plasma from ME patients (2).

Alpha-N-phenylacetyl-L-glutamine was increased in plasma from ME patients (5).

Figure of urea cycle and ammonia excretion pathways (14):

What is going on with nitrogen excretion and CPS1 in ME?


1) Semba et al. Environmental Enteric Dysfunction is Associated with Carnitine Deficiency and Altered Fatty Acid Oxidation. EBioMedicine. 2017 Mar;17:57-66. doi: 10.1016/j.ebiom.2017.01.026. Epub 2017 Jan 18.

2) Germain et al: Metabolic profiling of a ME/CFS discovery cohort reveals disturbances in fatty acid and lipid metabolism. Mol. BioSyst. 2017, 13, 371!divAbstract

3) Germain et al: Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology. Metabolites. 2018 Dec 6;8(4). pii: E90. doi: 10.3390/metabo8040090.

4) Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N et al (2016) Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A 113:E5472–E5480. 

5) Nagy-Szakal et al: Insights into ME/CFS phenotypes through comprehensive metabolomics. Nat. Sci. Rep, 2018, 8.

6) Wanders et al: Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans. FEBS J. 2011 Jan;278(2):182-94. doi: 10.1111/j.1742-4658.2010.07947.x. Epub 2010 Dec 13.

7) Guuerrero et al: Laboratory diagnostic approaches in metabolic disorders. Ann Transl Med. 2018 Dec;6(24):470. doi: 10.21037/atm.2018.11.05.

8) Lheureux et al: Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Crit Care. 2005 Oct 5;9(5):431-40. Epub 2005 Jun 10.

9) Yamano et al: Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Sci Rep. 2016 Oct 11;6:34990. doi: 10.1038/srep34990.

10) Monro and Puri: A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications
Mol Neurobiol. 2018 Sep;55(9):7377-7388. doi: 10.1007/s12035-018-0928-9. Epub 2018 Feb 6.

11) Nakagawa et al: SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009 May 1;137(3):560-70. doi: 10.1016/j.cell.2009.02.026.

12) Nakagawa T1, Guarente L. Urea cycle regulation by mitochondrial sirtuin, SIRT5. Aging (Albany NY). 2009 Jun 29;1(6):578-81.

13) Matone et al. Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance. PLoS One. 2016 Mar 3;11(3):e0150495. doi: 10.1371/journal.pone.0150495. eCollection 2016.

14) Miesel et al: Sodium benzoate for treatment of hepatic encephalopathy. Gastroenterol Hepatol (N Y). 2013 Apr;9(4):219-27.

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