Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are maintained at low levels by regulated production and efficient removal of these thiols. The regulation of the metabolism of methionine and Cys is discussed from the standpoint of maintaining low levels of Hcy and Cys while, at the same time, ensuring an adequate supply of these thiols for their essential functions. S-Adenosylmethionine coordinately regulates the flux through remethylation and transsulfuration, and glycine N-methyltransferase regulates flux through transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio. Cystathionine beta-synthase activity is also regulated in response to the redox environment, and transcription of the gene is hormonally regulated in response to fuel supply (insulin, glucagon, and glucocorticoids). The H2S-producing capacity of cystathionine gamma-lyase may be regulated in response to nitric oxide. Cys is substrate for a variety of anabolic and catabolic enzymes. Its concentration is regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is upregulated in a Cys-responsive manner via a decrease in the rate of polyubiquitination and, hence, degradation by the 26S proteasome.

SULFUR AMINO ACID METABOLISM: Pathways for Production and Removal of Homocysteine and Cysteine

Hallervorden-Spatz syndrome (HSS) is an autosomal recessive neurodegenerative disorder associated with iron accumulation in the brain. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals iron deposits in the basal ganglia. In this respect, HSS may serve as a model for complex neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, Huntington disease and human immunodeficiency virus (HIV) encephalopathy, in which pathologic accumulation of iron in the brain is also observed. Thus, understanding the biochemical defect in HSS may provide key insights into the regulation of iron metabolism and its perturbation in this and other neurodegenerative diseases. Here we show that HSS is caused by a defect in a novel pantothenate kinase gene and propose a mechanism for oxidative stress in the pathophysiology of the disease.

A novel pantothenate kinase gene ( PANK2 ) is defective in Hallervorden-Spatz syndrome

We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by (1)H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.

/pdf/pharmacometabonomic-identification-of-a-significant-host-2t013602jp.pdf

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Parkinson's disease evolves slowly, and there is current interest in exploring the earliest stages of the disorder, because of new approaches to studying pathogenesis and developing potential neuroprotective treatment. Recognizing early Parkinson's disease is not easy. The certainty of diagnosis increases as the disease advances. To address the problem of identifying Parkinson's disease in its initial phases of clinical expression, we propose the following designated levels of confidence for the diagnosis: (1) clinically possible, (2) clinically probable, and (3) clinically definite. Laboratory support for the diagnosis may be applied to each category. Criteria are provided as a framework underpinning this classification.

Criteria for diagnosing Parkinson's disease.

Background Olfactory deficits in Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) have been well established. Objective To clarify and review the literature by evaluating the evidence for olfactory deficits in 3 olfactory domains, including odor identification, recognition, and detection threshold. Data Sources A literature search of English-language studies of olfaction in AD, PD, and healthy controls was conducted via online databases (PsycInfo and MEDLINE) and reference lists from review articles. Study Selection To meet selection criteria for meta-analysis, each study required a control group and complete and usable data. This review yielded 26 publications of olfactory identification, recognition, and/or detection threshold. Because of the inclusion of more than 1 relevant study of olfaction in several of these publications (eg, both identification and threshold assessed), 43 studies were ultimately appropriate for meta-analysis. Data Extraction Effect sizes were calculated for each study by expressing differences between patient and control group means in SD units (Cohen's d ). Data Synthesis Extremely large effect sizes were shown across all tasks in both AD and PD groups. Both between-group analyses using the Mann-Whitney U test and within-group analyses using Friedman 2-way analysis of variance did not reveal any significant differences (all P >.30). Conclusions As expected, severe deficits were found for both patients with AD and PD in each of the 3 olfactory domains relative to controls. However, no discriminating olfactory deficits were seen between patient groups or among the 3 measured olfactory domains, suggesting a similar disturbance in olfactory function between patients with AD and PD.

https://jamanetwork.com/journals/jamaneurology/articlepdf/773547/noc7055.pdf

Olfaction in Neurodegenerative Disease: A Meta-analysis of Olfactory Functioning in Alzheimer's and Parkinson's Diseases

Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease.

1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with Parkinson's disease, motor neurone disease and to age-matched controls.2. At this low dose level the controls excreted proportionately more sulphate and less glucuronide conjugate than has been reported for administration of 1000 mg of paracetamol.3. Both groups of patients with chronic neurological disease excreted decreased amounts of paracetamol sulphate (control mean 11.2±5.4% dose; Parkinson's disease 3.9±3.7%; motor neurone disease, 5.0±4.1%).4. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6±11.7 in controls, but 1.1±1.7 and 1.2±1.7 in Parkinson's disease and motor neurone disease respectively. These differences are statistically significant (p<0.001).

Metabolism of low-dose paracetamol in patients with chronic neurological disease.

Pathways of cysteine metabolism in MND/ALS

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Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease.

Metabolism of low-dose paracetamol in patients with chronic neurological disease.

Pathways of cysteine metabolism in MND/ALS