Enzymatic and biochemical properties of a novel human serine dehydratase isoform

Ogawa, Hirofumi; Gomi, Tomoharu; Nishizawa, Mikio; Hayakawa, Yumiko; Endo, Shunro; Hayashi, Kyoko; Ochiai, Hiroshi; Takusagawa, Fusao; Pitot, Henry C.; Mori, Hisashi; Sakurai, Hiroaki; Koizumi, Keiichi; Saiki, Ikuo; Oda, Hitomi; Fujishita, Takashi; Miwa, Takeshi; Maruyama, Muneharu; Kobayashi, Masashi

doi:10.1016/j.bbapap.2006.02.010

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…(7) Glc →→→ 3-PG →Php (catalyzed by phosphoglycerate dehydrogenase); Php + Ala (or Glu) → Pser + pyruvate (or →Kg); the latter reaction is catalyzed by phosphoserine aminotransferase; Pser → Ser → pyruvate, catalyzed by serine dehydratase (Ogawa et al, 2006) or serine dehydratase-like (SDSL) (Ogawa et al, 2006). Notably, SDS was reported to be absent from human colon carcinomas (Snell et al, 1988).…”

Section: Pathways Leading To Pyruvate Commencing From Glucose: Intermmentioning

confidence: 99%

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

Chinopoulos

2020

Front. Physiol.

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A metabolic hallmark of many cancers is the increase in glucose consumption coupled to excessive lactate production. Mindful that L-lactate originates only from pyruvate, the question arises as to how can this be sustained in those tissues where pyruvate kinase activity is reduced due to dimerization of PKM2 isoform or inhibited by oxidative/nitrosative stress, posttranslational modifications or mutations, all widely reported findings in the very same cells. Hereby 17 pathways connecting glucose to lactate bypassing pyruvate kinase are reviewed, some of which transit through the mitochondrial matrix. An additional 69 converging pathways leading to pyruvate and lactate, but not commencing from glucose, are also examined. The minor production of pyruvate and lactate by glutaminolysis is scrutinized separately. The present review aims to highlight the ways through which L-lactate can still be produced from pyruvate using carbon atoms originating from glucose or other substrates in cells with kinetically impaired pyruvate kinase and underscore the importance of mitochondria in cancer metabolism irrespective of oxidative phosphorylation.

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Section: Pathways Leading To Pyruvate Commencing From Glucose: Intermmentioning

confidence: 99%

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

Chinopoulos

2020

Front. Physiol.

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“…We note that this pentapeptide sequence fragment is well-conserved in rSDH and in the SDHs of other species. 1,18,[66][67][68][69][70][71] The residues have stabilizing effects on all three major transition states (around -1.0 kcal mol -1 for TS1, -2.5∼-3.5 kcal mol -1 for TS2-2 and -5∼-8 kcal mol -1 for TS3), except that Ser64 and Asn67 have small (1.4∼1.5 kcal mol -1 ) destabilization effects on TS2-2. The moderate transition state-stabilizing effects on TS1 can be caused by the small increases in the negative charges on the carboxyl group, resulted from proton transfer from serine to the phosphate.…”

Section: Strategy For Transition State Stabilizationmentioning

confidence: 99%

A Quantum Mechanical/Molecular Mechanical Study on the Catalysis of the Pyridoxal 5′-Phosphate-Dependent Enzyme l-Serine Dehydratase

Zhao

2008

J. Phys. Chem. B

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The catalytic mechanism of a pyridoxal 5'-phosphate-dependent enzyme, l-serine dehydratase, has been investigated using ab initio quantum mechanical/molecular mechanical (QM/MM) methods. New insights into the chemical steps have been obtained, including the chemical role of the substrate carboxyl group in the Schiff base formation step and a proton-relaying mechanism involving the phosphate of the cofactor in the beta-hydroxyl-leaving step. The latter step is of no barrier and follows sequentially after the elimination of the alpha-proton, leading to a single but sequential alpha, beta-elimination step. The rate-limiting transition state is specifically stabilized by the enzyme environment. At this transition state, charges are localized on the substrate carboxyl group, as well as on the amino group of Lys41. Specific interactions of the enzyme environment with these groups are able to lower the activation barrier significantly. One major difficulty associated with studies of complicated enzymatic reactions using ab initio QM/MM models is the appropriate choices of reaction coordinates. In this study, we have made use of efficient semiempirical models and pathway optimization techniques to overcome this difficulty.

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“…SDH-like (SDHL, also abbreviated SDSL), which shares approximately 60% amino acid sequence with SDH, was deposited into mammalian databases as a protein of unknown function. SDHL has SDH activity toward L-Ser and L-threonine (L-Thr) [41,42], but it remains unclear whether mammalian SDHL exhibits amino acid racemase activity.…”

Section: Introductionmentioning

confidence: 99%

Identification of an l-serine/l-threonine dehydratase with glutamate racemase activity in mammals

Katane

Nakasako

Yako

et al. 2020

Biochemical Journal

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Recent investigations have shown that multiple D-amino acids are present in mammals and these compounds have distinctive physiological functions. Free D-glutamate is present in various mammalian tissues and cells and in particular itis presumably correlated with cardiac function, and much interest is growing in its unique metabolic pathways. Recently, we first identified D-glutamate cyclase as its degradative enzyme in mammals, whereas its biosynthetic pathway in mammals is unclear. Glutamate racemase is a most probable candidate, which catalyzes interconversion between D-glutamate and L-glutamate. Here, we identified the cDNA encoding L-serine dehydratase-like (SDHL) as the first mammalian clone with glutamate racemase activity. This rat SDHL had been deposited in mammalian databases as a protein of unknown function and its amino acid sequence shares approximately 60% identity with that of L-serine dehydratase. Rat SDHL was expressed in Escherichia coli, and the enzymatic properties of the recombinant were characterized. The results indicated that rat SDHL is a multifunctional enzyme with glutamate racemase activity in addition to L-serine/L-threonine dehydratase activity. This clone is hence abbreviated as STDHgr. Further experiments using cultured mammalian cells confirmed that D-glutamate was synthesized and L-serine and L-threonine were decomposed. It was also found that SDHL (STDHgr) contributes to homeostasis of several other amino acids.

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Enzymatic and biochemical properties of a novel human serine dehydratase isoform

Cited by 10 publications

References 24 publications

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

A Quantum Mechanical/Molecular Mechanical Study on the Catalysis of the Pyridoxal 5′-Phosphate-Dependent Enzyme l-Serine Dehydratase

Identification of an l-serine/l-threonine dehydratase with glutamate racemase activity in mammals

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