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Peroxisomal L-pipecolic acid oxidation is deficient in liver from Zellweger syndrome patients
S J Mihalik1, H W Moser, P A Watkins
1Department of Pediatrics, University of Iowa, Iowa City 52242.
Insights
L-pipecolic acid accumulates in infants with peroxisomal disorders due to defective oxidation. This study confirms impaired L-pipecolic acid oxidation in Zellweger syndrome livers, identifying a key metabolic defect.
Area of Science:
- Biochemistry
- Cell Biology
- Medical Genetics
Background:
- L-pipecolic acid, a lysine degradation product, is elevated in infants with generalized peroxisomal disorders like Zellweger syndrome.
- Peroxisomal disorders disrupt essential cellular functions, leading to the accumulation of specific metabolites.
Purpose of the Study:
- To investigate the role of peroxisomes in L-pipecolic acid metabolism.
- To determine if impaired L-pipecolic acid oxidation is a characteristic feature of Zellweger syndrome.
Main Methods:
- Separation of human liver organelles using Percoll gradients.
- Measurement of L-[3H]pipecolic acid oxidation to alpha-[3H]aminoadipic acid (AAA).
- Assay of L-pipecolic acid oxidation activity in liver specimens from controls and Zellweger syndrome patients.
Main Results:
- L-pipecolic acid oxidation activity in normal human liver fractions correlated with the peroxisomal marker catalase.
- Oxidation was not inhibited by mitochondrial inhibitors and produced hydrogen peroxide, indicating a peroxisomal oxidase.
- Liver homogenates from Zellweger syndrome patients exhibited significantly reduced L-pipecolic acid oxidation compared to controls.
Conclusions:
- L-pipecolic acid oxidation occurs primarily in peroxisomes.
- Defective peroxisomal oxidation of L-pipecolic acid is a likely cause for its accumulation in Zellweger syndrome.
- This finding highlights a specific metabolic dysfunction in peroxisomal disorders.
Abstract:
L-Pipecolic acid, a cyclic imino acid produced during the degradation of lysine, accumulates in body fluids of infants with the generalized peroxisomal disorders, including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Peroxisome-enriched fractions from normal human liver oxidized L-[3H]pipecolic acid to alpha-[3H]aminoadipic acid (AAA). When human liver organelles were separated on a Percoll gradient, L-[3H]pipecolic acid oxidation activity (as measured by [3H]AAA formation) most closely segregated with the peroxisomal marker, catalase, and was not associated with the mitochondria. L-Pipecolic acid oxidation was not inhibited by antimycin A and rotenone and produced H2O2, consistent with its involving a peroxisomal oxidase. We measured L-pipecolic acid oxidation in liver specimens from patients with peroxisomal disorders. While liver homogenates from adult (n = 5) and infant (n = 10) controls formed 47.1 +/- 6.6 and 48.3 +/- 10.0 pmol AAA/mg protein/h, respectively, Zellweger syndrome livers (n = 8) formed only 1.7 +/- 0.3 pmol AAA/mg protein/h. L-pipecolic acid oxidation in normal infant livers was low at birth and increased with age, but Zellweger syndrome livers showed little activity at any age. Thus, the high circulating levels of L-pipecolic acid in Zellweger syndrome probably result from defective peroxisomal oxidation of L-pipecolic acid to AAA.