The occurrence of Macrozamin in the seeds of Cycads

Riggs, NV

doi:10.1071/ch9540123

Cited by 29 publications

(14 citation statements)

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“…It is not clear how S-nitrosation of Cys-␤93 increases the oxygen affinity on a molecular level. Although blocking this residue by alkylation has similar effects on the oxygen affinity, these data also show that unlike S-nitrosation, maximal increases in the oxygen affinity are only attained after both Cys-␤93 residues are blocked by N-ethylmaleimide (24).…”

mentioning

confidence: 74%

“…However, since the hypothesis requires that only the deoxygenated conformer of Hb release NO (13,14), then the oxygen affinity of SNO-Hb (despite its low concentration) is critical to the role of Hb as an NO carrier. This is an important issue because previous studies on the role of Cys-␤93 have shown that blockage of the thiol via alkylation or the formation of mixed disulfides increases the oxygen affinity of Hb (24,25). Furthermore, the naturally occurring Hb variant Hb Okazaki, where Cys-␤93 is substituted with an arginine residue, also has an increased oxygen affinity (26).…”

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confidence: 99%

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Biochemical Characterization of HumanS-Nitrosohemoglobin

Patel¹,

Hogg²,

Spencer³

et al. 1999

Journal of Biological Chemistry

130

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S-Nitrosation of cysteine ␤93 in hemoglobin (S-nitrosohemoglobin (SNO-Hb)) occurs in vivo, and transnitrosation reactions of deoxygenated SNO-Hb are proposed as a mechanism leading to release of NO and control of blood flow. However, little is known of the oxygen binding properties of SNO-Hb or the effects of oxygen on transnitrosation between SNO-Hb and the dominant low molecular weight thiol in the red blood cell, GSH. These data are important as they would provide a biochemical framework to assess the physiological function of SNO-Hb. Our results demonstrate that SNO-Hb has a higher affinity for oxygen than native Hb. This implies that NO transfer from SNO-Hb in vivo would be limited to regions of extremely low oxygen tension if this were to occur from deoxygenated SNOHb. Furthermore, the kinetics of the transnitrosation reactions between GSH and SNO-Hb are relatively slow, making transfer of NO ؉ from SNO-Hb to GSH less likely as a mechanism to elicit vessel relaxation under conditions of low oxygen tension and over the circulatory lifetime of a given red blood cell. These data suggest that the reported oxygen-dependent promotion of S-nitrosation from SNO-Hb involves biochemical mechanisms that are not intrinsic to the Hb molecule.

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confidence: 74%

mentioning

confidence: 99%

Biochemical Characterization of HumanS-Nitrosohemoglobin

Patel¹,

Hogg²,

Spencer³

et al. 1999

Journal of Biological Chemistry

130

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“…In addition to modifying the thiol residues of hemoglobin, NEM modification of the ␤93 cysteinyl residue also stabilizes hemoglobin in the so-called "R"-state or high oxygen-affinity state (11). The rates of GSNO decay and GSH formation were slightly faster when NEM-treated hemoglobin was used, suggesting that the kinetics of this reaction are related to the conformation of the hemoglobin tetramer.…”

Section: Methodsmentioning

confidence: 96%

Reaction of S-Nitrosoglutathione with the Heme Group of Deoxyhemoglobin

Spencer¹,

Zeng²,

Patel³

et al. 2000

Journal of Biological Chemistry

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The mechanism of interaction between S-nitrosoglutathione (GSNO) and hemoglobin is a crucial component of hypotheses concerning the role played by S-nitrosohemoglobin in vivo. We previously demonstrated (Patel, R. P., Hogg, N., Spencer, N. Y., Kalyanaraman, B., Matalon, S., and Darley-Usmar, V. M. (1999) J. Biol. Chem. 274, 15487-15492) that transnitrosation between oxygenated hemoglobin and GSNO is a slow, reversible process, and that the reaction between GSNO and deoxygenated hemoglobin (deoxyHb) did not conform to second order reversible kinetics. In this study we have reinvestigated this reaction and show that GSNO reacts with deoxyHb to form glutathione, nitric oxide, and ferric hemoglobin. Nitric oxide formed from this reaction is immediately autocaptured to form nitrosylated hemoglobin. GSNO reduction by deoxyHb is essentially irreversible. The kinetics of this reaction depended upon the conformation of the protein, with more rapid kinetics occurring in the high oxygen affinity state (i.e. modification of the Cys␤-93) than in the low oxygen affinity state (i.e. treatment with inositol hexaphosphate). A more rapid reaction occurred when deoxymyoglobin was used, further supporting the observation that the kinetics of reduction are directly proportional to oxygen affinity. This observation provides a mechanism for how deoxygenation of hemoglobin/myoglobin could facilitate nitric oxide release from Snitrosothiols and represents a potential physiological mechanism of S-nitrosothiol metabolism. The interaction between S-nitrosoglutathione (GSNO)1 and hemoglobin has become an area of intense interest due to the discovery that circulating erythrocytes contain measurable levels of S-nitrosohemoglobin (HbSNO) (1), and that the combination of S-nitrosohemoglobin and glutathione (GSH) will relax vessels in an oxygen sensitive manner (2). HbSNO is a posttranslationally modified form of hemoglobin that contains a nitrosated cysteinyl residue at the ␤-93 position. The mechanism for the formation of HbSNO in vivo remains unknown, and the functional consequences of this modification are the subject of intense debate (1-4). It has been suggested that S-nitrosation of Hb represents an oxygen-sensitive mechanism to control vascular tone (1). The crux of this hypothesis is that transnitrosation, i.e. the chemical transfer of the nitroso group, between Hb and GSH is an oxygen-sensitive reaction in which deoxygenation of Hb allows the eventual formation of GSNO, which may then act as a vasodilator. The mechanism by which intra-erythrocyte GSNO acts as a vasodilator is as yet unknown. In a new twist to this hypothesis it has recently been suggested that rapid transnitrosation to form GSNO would be fatal, due to a massive vasodilatory response upon deoxygenation of Hb (5). In order to avoid such an outcome the majority of the NO has been proposed to be autocaptured at the deoxygenated heme, to give nitrosyl hemoglobin (HbNO), in which nitric oxide is bound to the iron of ferrous hemoglobin. It has been additionally suggested that...

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“…Early studies by Riggs demonstrated that covalent modification of thiols in human and horse hemoglobin results in increased affinity of hemoglobin to O 2 and that oxygen binding results in increased thiol reactivity, which in human hemoglobin occurs on the ␤ chains (30,31). Nitrosation is another form of covalent thiol modification, and so it is not surprising that, like alkylation, nitrosative reactivity of the cys␤93 would be affected by the allosterically controlled exposure of the thiol residue, as demonstrated by Jia et al (5).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions

Joshi

Ferguson

Han

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

194

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Although irreversible reaction of NO with the oxyheme of hemoglobin (producing nitrate and methemoglobin) is extremely rapid, it has been proposed that, under normoxic conditions, NO binds preferentially to the minority deoxyheme to subsequently form S-nitrosohemoglobin (SNOHb). Thus, the primary reaction would be conservation, rather than consumption, of nitrogen oxide. Data supporting this conclusion were generated by using addition of a small volume of a concentrated aqueous solution of NO to a normoxic hemoglobin solution. Under these conditions, however, extremely rapid reactions can occur before mixing. We have thus compared bolus NO addition to NO generated homogeneously throughout solution by using NO donors, a more physiologically relevant condition. With bolus addition, multiple hemoglobin species are formed (as judged by visible spectroscopy) as well as both nitrite and nitrate. With donor, only nitrate and methemoglobin are formed, stoichiometric with the amount of NO liberated from the donor. Studies with increasing hemoglobin concentrations reveal that the nitrite-forming reaction (which may be NO autoxidation under these conditions) competes with reaction with hemoglobin. SNOHb formation is detectable with either bolus or donor; however, the amounts formed are much smaller than the amount of NO added (less than 1%). We conclude that the reaction of NO with hemoglobin under normoxic conditions results in consumption, rather than conservation, of NO. O ne of the most important experimental findings that led to the postulate that the endothelium-derived relaxing factor (EDRF) is identical to nitric oxide (nitrogen monoxide, NO) was the demonstration that endothelium-dependent relaxation is exquisitely sensitive to inhibition by hemoglobin, which rapidly reacts with NO (1). Curiously, however, even though very small concentrations of hemoglobin are quite potent in preventing EDRF-dependent relaxation, little attention was initially paid to the problem this raises with the NO͞EDRF hypothesis, namely, that in vivo NO is produced immediately adjacent to a pool of very high (mM) concentrations of hemoglobin, which will act as a potent sink for the NO, thus decreasing its concentration at all locations and preventing it from reaching a physiologically functional level. Mathematical modeling has illustrated the validity of this concept (2-4).There have emerged two hypotheses to explain how NO might still function as EDRF. According to one (5-10), rather than irreversibly consuming NO, hemoglobin actually conserves it, in the form of a nitrosothiol moiety, and the linkage of the accessibility͞ reactivity of the thiol group involved (␤cys93) to the oxygenationdependent allosteric transitions in hemoglobin establishes a respiratory cycle whereby NO and O 2 are simultaneously taken up in the lung and then delivered to the tissue during the arterial͞venous transit. Thus, hemoglobin would deliver to oxygen-deficient vascular beds not only the oxygen required for sustained metabolism but also a vasodilator (NO).Th...

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The occurrence of Macrozamin in the seeds of Cycads

Abstract: CYCADS* Macrozamin was shown by Cooper (1940) to be the toxic principle of Macroxamia spiralis Miq., a New South Wales cycad. It was later obtained from the Western Australian M. reidlei C. A. Gard. (Lythgoe and Riggs 1949) and shown to be I or I1 (Langley, Lythgoe, and Riggs 1951).

Cited by 29 publications

References 1 publication

Biochemical Characterization of HumanS-Nitrosohemoglobin

Biochemical Characterization of HumanS-Nitrosohemoglobin

Reaction of S-Nitrosoglutathione with the Heme Group of Deoxyhemoglobin

Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions

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