Molybdenum Cofactor Deficiency: Metabolic Link Between Taurine and S-Sulfocysteine - Advances in Experimental Medicine and Biology - page 12

SSC S-sulfocysteine
HPLC High-performance liquid chromatography
2.1 Introduction
Molybdenum cofactor deficiency (MoCD) is a rare inherited metabolic disorder
(Johnson et al. 1980 ; Johnson and Duran 2001 ) caused by defects in the biosyn-
thesis of the molybdenum cofactor (Moco) leading to the simultaneous loss of
activities of all molybdenum-dependent enzymes: sulfite oxidase, xanthine dehy-
drogenase, aldehyde oxidase, and the mitochondrial amidoxime-reducing compo-
nent (Schwarz et al. 2009 ). Affected patients exhibit severe neurological
abnormalities, such as microcephaly and seizures, and they usually die in early
childhood (Johnson and Duran 2001 ) . Sul fi te oxidase de fi ciency (SOD) is less
frequent but clinically indistinguishable from MoCD, which renders sulfite oxi-
dase as the most important Moco enzyme in humans (Tan et al. 2005 ) . Sul fi te
oxidase catalyzes the oxidation of sulfite, which is generated throughout the
catabolism of sulfur-containing amino acids, to sulfate (Griffith 1987 ; Johnson
and Duran 2001 ). Deficiencies of Moco and sulfite oxidase result in the accumula-
tion of sulfite, a highly toxic molecule that breaks disulfide bridges in proteins and
cystine, thereby affecting many protein and cellular functions (Zhang et al. 2004 ) .
Sulfite accumulation is accompanied by the formation of secondary metabolites
such as thiosulfate and S-sulfocysteine (SSC) (Johnson and Duran 2001 ) , which
together with reduced homocysteine levels (Sass et al. 2004 ) are common bio-
chemical indicators for MoCD and SOD.
Sulfite is generated throughout the catabolism of sulfur-containing amino acids
in two steps. First, the cytosolic enzyme cysteine dioxygenase catalyzes the forma-
tion of cysteine sulfinic acid (CSA). Second, either CSA undergoes a transamina-
tion in mitochondria, which leads to the formation of sulfite, or it is decarboxylated
in the cytosol leading to the formation of hypotaurine, which is further oxidized to
taurine. In MoCD sulfite first accumulates in liver, where most of the catabolism of
sulfur-containing amino acids takes place. Subsequently, accumulation of sulfite in
plasma is detectable and finally sulfite crosses the blood-brain barrier triggering a
devastating and progressive neuronal damage (Schwarz et al. 2009 ) .
Using a knockout animal model for MoCD (Lee et al. 2002 ) a substitution ther-
apy with cyclic pyranopterin monophosphate has been established (Schwarz et al.
2004 ) and recently a first successful treatment for an MoCD (type A) patient has
been reported (Veldman et al. 2010 ). Before treatment was initiated, a manifested
rapid increase of urinary sulfite, thiosulfate, and SSC values was recorded. However,
within few days after treatment was initiated, a remarkable normalization of all
MoCD biomarkers as well as a significant clinical improvement of the patient were
observed. Recently, we reported the development of a new HPLC method for diag-
nosis and treatment monitoring of MoCD patients, which enables an accurate and
sensitive measurement of urinary as well as serum SSC levels and is being currently
used to diagnose the disease to monitor treated patients (Belaidi et al. 2011 ) .