Cloning and Mapping of the cDNA for Human Sarcosine Dehydrogenase, a Flavoenzyme Defective in Patients with Sarcosinemia

Eschenbrenner, Michel; Jörns, Marilyn Schuman

doi:10.1006/geno.1999.5886

Cited by 28 publications

(19 citation statements)

References 33 publications

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“…Sarcosine treatment seems well tolerated with few side effects. Long-term use of sarcosine is presumed to be safe given that sarcosenemia, a rare autosomal recessive metabolic disorder characterized by an increased concentration of sarcosine in blood and urine, is considered to be a relatively benign condition [10;21]. Therefore, characteristics of sarcosine in reducing nociceptive behavior in multiple rodent models, in inducing immediate analgesia and anti-neuropathy, together with potentiation of anti-neuropathic effects with repeated use, and coupled with human evidence of minimal side effects with long term use at large doses, all suggest that it should be considered as candidate therapeutic approach for clinical management of chronic pain.…”

Section: Discussionmentioning

confidence: 99%

Prefrontal cortex and spinal cord mediated anti-neuropathy and analgesia induced by sarcosine, a glycine-T1 transporter inhibitor

Centeno

Mutso

Millecamps

et al. 2009

Pain

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Sarcosine is a competitive inhibitor of glycine type 1 transporter. We hypothesized that it may have analgesic and anti-neuropathic efficacy by a dual action: affecting neurotransmission in the prefrontal cortex as well as within the spinal cord. In rats with spared nerve injury (SNI) oral sarcosine reduced mechanical sensitivity for the injured limb (anti-neuropathy or anti-allodynia) as well as for the uninjured limb (analgesia), showing better dose efficacy for the injured limb. Intrathecal administration of sarcosine was more effective in reducing mechanical sensitivity for the uninjured paw. In contrast, prefrontal cortex infusions of sarcosine acutely reduced mechanical sensitivity for the injured paw. Repeated daily oral sarcosine induced anti-neuropathy, observed only after days of repeated treatment; this long term effect disappeared a few days after treatment cessation. The findings indicate that manipulating glycine T1 transporter at multiple central sites can induce acute analgesia, as well as acute and long-term reduction in neuropathic pain behavior. Analgesic effects seem primarily mediated through spinal cord circuitry while anti-neuropathic effects through prefrontal cortex circuitry, most likely through distinct molecular pathways. The results suggest that such an approach may provide a novel venue for treating clinical pain conditions.

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Section: Discussionmentioning

confidence: 99%

Prefrontal cortex and spinal cord mediated anti-neuropathy and analgesia induced by sarcosine, a glycine-T1 transporter inhibitor

Centeno

Mutso

Millecamps

et al. 2009

Pain

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“…The oxidized RS-NO product could then form in the presence of an electron acceptor (21), and in sarcosine dehydrogenase, the bound FAD may fulfill this requirement. The enzyme has 20 cysteines, one of which is located (in the 1°sequence) within the flavin-binding domain (62). Although there is no known role for a thiol in the enzymatic activity of SarDH, the modest inhibition by CysNO suggests that NO ϩ may modify an allosteric site.…”

Section: Discussionmentioning

confidence: 99%

New Insights into Protein S-Nitrosylation

Foster

Stamler

2004

Journal of Biological Chemistry

163

105

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The biological effects of nitric oxide (NO) are in significant part mediated through S-nitrosylation of cysteine thiol. Work on model thiol substrates has raised the idea that molecular oxygen (O 2 ) is required for Snitrosylation by NO; however, the relevance of this mechanism at the low physiological pO 2 of tissues is unclear. Here we have used a proteomic approach to study S-nitrosylation reactions in situ. We identify endogenously S-nitrosylated proteins in subcellular organelles, including dihydrolipoamide dehydrogenase and catalase, and show that these, as well as hydroxymethylglutaryl-CoA synthase and sarcosine dehydrogenase (SarDH), are S-nitrosylated by NO under strictly anaerobic conditions. S-Nitrosylation of SarDH by NO is best rationalized by a novel mechanism involving the covalently bound flavin of the enzyme. We also identify a set of mitochondrial proteins that can be S-nitrosylated through multiple reaction channels, including anaerobic/oxidative, NO/O 2 , and GSNO-mediated transnitrosation. Finally, we demonstrate that steady state levels of S-nitrosylation are higher in mitochondrial extracts than the intact organelles, suggesting the importance of denitrosylation reactions. Collectively, our results provide new insight into the determinants of S-nitrosothiol levels in subcellular compartments.

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“…Sarcosinemia caused by a deficiency of SARDH [17] is also a rare metabolic disorder characterized by elevated levels of sarcosine in plasma and urine. The mutational frequency in the human SARDH gene apparently varies from 1:350000 to 1:3414.…”

Section: Flavoenzymes In Cofactor Biogenesis and Metabolismmentioning

confidence: 99%