Tiglylglycine excreted in urine in disorders of isoleucine metabolism and the respiratory chain measured by stable isotope dilution GC-MS

Abstract

Tiglyglycine (TG), an intermediate product of the catabolism of isoleucine, is increased in the urine of patients with beta-ketothiolase deficiency or with disorders of propionate metabolism. It is also implicated as a useful diagnostic marker in disorders of the respiratory chain. We present a method for the synthesis of TG and tiglyl[13C, 15N]glycine and the development of a stable isotope dilution mass spectrometric assay for TG. We compare data from controls with that from subjects with beta-ketothiolase deficiency and propionyl-CoA carboxylase deficiency, and with six patients with enzyme-confirmed disorders of the respiratory chain. TG was increased in the urine from all of the patient groups. The increased TG excretion did not persist in one patient with a respiratory chain defect, which suggests that, in some patients, multiple sample analysis may be necessary to identify a respiratory chain defect. This is the first urinary compound to be implicated as a potential marker of disorders of the respiratory chain.

Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2

“…A third patient was found to have mitochondrial dysfunction through the Cleveland Clinic with a low CoQ10 ratio, who improved with nutritional supplementation. Checking levels of amino acids, organic acids, ammonia, lactate/pyruvate ratios, creatinine phosphokinase (CPK), free/total carnitine ratios, and CoQ10 and tiglyglycine levels (a marker for mitochondrial respiratory chain disorders) can also be useful to evaluate mitochondrial function [215,216].…”

Impaired ubiquitin‐proteasome‐mediated PGC‐1α protein turnover and induced mitochondrial biogenesis secondary to complex‐I deficiency

“…As the mitochondrial CoA pool is limited in size [], inhibition of FAO and subsequent accumulation of acyl‐CoA esters may lead to sequestration of CoA, thereby inhibiting other intramitochondrial CoA‐dependent enzymes like the branched‐chain alpha‐ketoacid dehydrogenase that catalyzes the second, committing step in BCAA degradation [], and methylmalonate semidaldehyde dehydrogenase that functions in valine catabolism []. Our demonstration that both mitochondrial FAO and BCAA degradation are inhibited in complex‐I‐deficient cells is in agreement with the frequently observed accumulation of intermediate metabolites of both processes in body fluids and eventually in urinary excretions of complex‐I‐deficient patients []. Interestingly, intracellular accumulation of fatty acids and their intermediate metabolites, which promote inhibition of mitochondrial ADP/ATP transport [], apoptosis [], and membrane damage [], is also implicated in type 2 diabetes and inborn errors of mitochondrial FAO, both of which share some clinical features with complex‐I deficiencies (e.g.…”

Acute and short-term administrations of delta-9-tetrahydrocannabinol modulate major gut metabolomic regulatory pathways in C57BL/6 mice

“…Reduction of 2E-methyl glutaconic acid and tiglyglycine was observed upon 1X administration. These metabolites are often detected in human urine samples when the catabolism of branched-chain amino acids (BCAA) (especially isoleucine) is impaired 70,71 , suggesting that THC possibly influences BCAA catabolism. Emerging evidence supports the importance of BCAA catabolism in lowering the risk of type-2 diabetes 72 .…”