CHAPTER ONE 1.0. INTRODUCTION AND LITERATURE REVIEW 1.1. INTRODUCTION One of the major metabolic enzymes that have gained so much interest of scientists is 3-Mercaptopyruvate sulfurtransferase (3-MST). This enzyme occurs widely in nature (Bordo, 2002 and Jarabak, 1981). It has been reported in several organisms ranging from humans to rats, fishes and insects. It is a mitochondrial enzyme which has been concerned in the detoxification of cyanide, a potent toxin of the mitochondrial respiratory chain (Nelson et al., 2000). Among the several metabolic enzymes that carry out xenobiotic detoxification, 3-mercaptopyruvate sulfurtransferase is of utmost importance. 3-mercaptopyruvate sulfurtransferase functions in the detoxifications of cyanide; mediation of sulfur ion transfer to cyanide or to other thiol compounds. (Vanden et al., 1967). It is also required for the biosynthesis of thiosulfate. In combination with cysteine aminotransferase, it contributes to the catabolism of cysteine and it is important in generating hydrogen sulphide in the brain, retina and vascular endothelial cells (Shibuya et al., 2009). It also acquired different functions such as a redox regulation (maintenance of cellular redox homeostasis) and defense against oxidative stress, in the atmosphere under oxidizing conditions Nagahara et al (2005). Hydrogen sulphide (H2S) is an important synaptic modulator, signalling molecule, smooth muscle contractor and neuroprotectant (Hosoki et al., 1997). Its production by the 3-mercaptopyruvate sulfurtransferase and cysteine aminotransferase pathways is regulated by calcium ions (Hosoki et al., 1997). Organisms that are exposed to cyanide poisoning usually have this enzyme in them. This could be in food as in the cyanogenic glucosides being consumed. It has been studied from variety of sources, which include bacteria, yeasts, plants, and animals (Marcus Wischik, 1998). Cyanide could be released into the bark of trees as a defence mechanism. There are array of defensive compounds that make their parts (leaves, flowers, stems, roots and fruits) distasteful or poisonous to predators. In response, however, the animals that feed on them have evolved over successive generations a range of measures to overcome these compounds and can eat the plant safely. The tree trunk offers a clear example of the variety of defences available to plants (Marcus Wischik, 1998). Oryctes rhinoceros larva is one of the organisms that are also exposed to cyanide toxicity because of the environment they are found. 1.2. 3-MERCAPTOPYRUVATE SULFURTRANSFERASE 3-Mercaptopyruvate sulfurtransferase (EC. 220.127.116.11), is a member of the group, Sulfurtransferases (EC 18.104.22.168 – 5), which are widely distributed enzymes of prokaryotes and eukaryotes (Bordo and Bork, 2002). 3-Mercaptopyruvate Sulfurtransferase is an enzyme that is part of the cysteine catabolic pathway. The enzyme catalyzes the conversion 3- mercaptopyruvate to pyruvate and H2S (Shibuya et al., 2009). The deficiency of this enzyme will result in elevated urine concentrations of 3-mercaptopyruvate as well as of 3-mercaptolactate, both in the form of disulfides with cysteine (Crawhall et al., 1969). It catalyzes the chemical reaction: 3-mercaptopyruvate + cyanide à pyruvate + thiocyanate 3-mercaptopyruvate + thiol à pyruvate + hydrogen sulphide (Sorbo 1957). It transfers sulfur-containing groups and participates in cysteine metabolism (Shibuya et al., 2013). This enzyme catalyzes the transfer of sulfane sulphur from a donor molecule, such as thiosulfate or 3- mercaptopyruvate, to a nucleophile acceptor, such as cyanide or mercptoethanol. 3-mercaptopyruvate is the known sulphur-donor substrate for 3-mercaptopyruvate sulfurtransferase (Porter & Baskin, 1995). 3-mercaptopyruvate sulfurtransferase is believed to function in the endogenous cyanide (CN) detoxification system because it is capable of transferring sulphur from 3-mercaptopyruvate (3-MP) to cyanide (CN), forming the less toxic thiocyanate (SCN) (Hylin and Wood, 1959). It is an important enzyme for the synthesis of hydrogen sulphide (H2S) in the brain (Shibuya et al., 2009). The systematic name of this enzyme class is 3-mercaptopyruvate: cyanide sulfurtransferase. It is also called beta-mercaptopyruvate sulfurtransferase (Vachek and Wood, 1972). It is one of three known H2S producing enzymes in the body (Hylin and Wood, 1959). It is primarily localised in the mitochondria (Cipollone et al., 2008). The expression levels of 3-MST in the brain during the fetal and postnatal periods are higher than those in the adult brain (unpublished data) although the promoter region shows characteristics of a typical housekeeping gene (Nagahara et al., 2004). The observation is supported by the finding that 3-MST expression in the cerebellum is decreased during the adult period (Shibuya et al., 2013). On the other hand, its expression level in the lung decreases from the perinatal period. These facts suggest that 3-MST could function in the fetal and postnatal brain. It was reported that serotonin signaling via the 5-HT1A receptor in the brain during the early developmental stage plays a critical role in the establishment of innate anxiety during the early developmental stage (Richardson-Jones et al., 2011). In rat, 3-MST possesses 2 redox-sensing molecular switches (Nagahara and Katayama, 2005). A catalytic-site cysteine and an intersubunit disulfide bond serve as a thioredoxin-specific molecular switch (Nagahara et al., 2007). The intermolecular switch is not observed in prokaryotes and plants, which emerged into the atmosphere under reducing conditions (Nagahara, 2013). As a result, it acquired different functions such as a redox regulation (maintenance of cellular redox homeostasis) and defense against oxidative stress, in the atmosphere under oxidizing conditions (Nagahara et al., 2005). Moreover, 3-MST can produce H2S (or HS−) as a biofactor (Shibuya et al., 2009), which cystathionine β-synthase and cystathionine γ-lyase also can generate (Abe and Kimura, 1996). Interestingly 3-MST can uniquely produce SOx in the redox cycle of persulfide formed at the low-redox catalytic-site cysteine (Nagahara et al., 2012). As an alternate hypothesis on the pathogenesis of the symptoms, H2S (or HS−) and/or SOx could suppress anxiety-like behavior, and therefore, defects in these molecules could increase anxiety-like behavior. However, no microanalysis method has been established to quantify H2S (or HS−) and SOx at the physiological level (Ampola et al., 1969). MCDU was first recognized and reported in 1968 as an inherited metabolic disorder caused by congenital 3-MST insufficiency or deficiency. Most cases were associated with mental retardation (Ampola et al, 1969) while the pathogenesis remains unknown. Human MCDU was reported to be associated with behavioral abnormalities, mental retardation (Crawhall, 1985), hypokinetic behaviour, and grand mal seizures and anomalies (flattened nasal bridge and excessively arched palate) (Ampola et al, 1969); however, the pathogenesis has not been clarified since MCDU was recognized more than 40 years ago. Macroscopic anomalies were associated in 1 case (Ampola et al, 1969); however, this could be an accidental combination. 3-MST deficiency also induced higher brain dysfunction in mice without macroscopic and microscopic abnormalities in the brain. 3-MST seems to play a critical role in the central nervous system, i.e., to establish normal anxiety (Richardson et al., 2011) 1.2.1. DISTRIBUTION 3-MST is widely distributed in prokaryotes and eukaryotes (Jarabak, 1981). It is localized in the cytoplasm and mitochondria, but not all cells contain 3-MST (Nagahara et al., 1998). 1.2.2. OCCURRENCE Human mercaptopyruvate sulfurtransferase (MPST; EC. 22.214.171.124) belongs to the family of sulfurtransferases (Vanden et al., 1967). These enzymes catalyze the transfer of sulfur to a thiophilic acceptor (Sorbo 1957), where MPST has a preference for 3-mercapto sulfurtransferase as the sulfur-donor. MPST plays a central role in both cysteine degradation and cyanide detoxification. In addition, deficiency in MPST activity has been proposed to be responsible for a rare inheritable disease known as mercaptolactate-cysteine disulfiduria (MCDU) (Hannestad et al, 2006). 1.2.3. MECHANISMS OF ACTION 3-Mercaptopyruvate sulfurtransferase catalyzes the reaction from mercaptopyruvate (SHCH2C (= O) COOH)) to pyruvate (CH3C (= O) COOH) in cysteine catabolism (Vackek and Wood, 1972). The enzyme is widely distributed in prokaryotes and eukaryotes (Jarabak, 1981). This disulfide bond serves as a thioredoxin-specific molecular switch. On the other hand, a catalytic-site cysteine is easily oxidized to form a low-redox potential sulfenate which results in loss of activity (Nahagara et al., 2005). Then, thioredoxin can uniquely restore the activity (Nagahara, 2013). Thus, a catalytic site cysteine contributes to redox-dependent regulation of 3-MST activity serving as a redox-sensing molecular switch (Nahagara, 2013). These findings suggest that 3-MST serves as an antioxidant protein and partly maintain cellular redox homeostasis. Further, it was proposed that 3-MST can produce hydrogen sulphide (H2S) by using a persulfurated acceptor substrate (Shibuya et al, 2009). As an alternative functional diversity of 3-MST, it has been recently demonstrated in-vitro that 3-MST can produce sulfur oxides (SOx) in the redox cycle of persulfide (S-S-) formed at the catalytic site of the reaction intermediate (Nagahara et al, 2012). 1.2.4. MOLECULAR FORMULA AND MOLECULAR WEIGHT The molecular formula of 3-MST is C3H4O3S (Vachek and Wood, 1972). 3-MST has a molecular weight of 120.127g/mol or 23800 Daltons (as summarized by PubChem compound).
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