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PubMed1999

Disruption of disulfide bonds exhibits differential effects on trafficking of regulated secretory proteins.

For several secretory proteins, it has been hypothesized that disulfide-bonded loop structures are required for sorting to secretory granules. To explore this hypothesis, we employed dithiothreitol (DTT) treatment in live pancreatic islets, as well as in PC-12 and GH(4)C(1) cells. In islets, disulfide reduction in the distal secretory pathway did not increase constitutive or constitutive-like secretion of proinsulin (or insulin). In PC-12 cells, DTT treatment caused a dramatic increase in unstimulated secretion of newly synthesized chromogranin B (CgB), presumably as a consequence of reducing the single conserved chromogranin disulfide bond (E. Chanat, U. Weiss, W. B. Huttner, and S. A. Tooze. EMBO J. 12: 2159-2168, 1993). However, in GH(4)C(1) cells that also synthesize CgB endogenously, DTT treatment reduced newly synthesized prolactin and blocked its export, whereas newly synthesized CgB was routed normally to secretory granules. Moreover, on transient expression in GH(4)C(1) cells, CgA and a CgA mutant lacking the conserved disulfide bond showed comparable multimeric aggregation properties and targeting to secretory granules, as measured by stimulated secretion assays. Thus the conformational perturbation of regulated secretory proteins caused by disulfide disruption leads to consequences in protein trafficking that are both protein and cell type dependent.

Animals↗
PubMed1995

Urinary excretion of free cystine and the tiopronin-cysteine-mixed disulfide during long term tiopronin treatment of cystinuria.

We report the results of a biochemical evaluation of long-term treatment of cystinuria with the SH compound tiopronin (2-mercaptopropionylglycine). The effects of tiopronin were studied by monitoring the urinary excretion of free cysteine and the mixed disulfide between tiopronin and cysteine. Thirty-one patients with homozygous cystinuria were treated with tiopronin for 0.4-12 years (mean 7.8 years). The urinary concentration of free cysteine was used to adjust the tiopronin dose. In 28 of the 31 patients a mean urinary cystine concentration of less than 1,200 mumol/1(288 mg/l) was achieved with the final dose. The final daily doses of tiopronin ranged from 250 mg (1.5 mmol) to 3,000 mg (18.4 mmol; mean 1,540 mg; 9.4 mmol). In a majority of the patients the treatment reduced the 24-hour urinary free cystine excretion effectively, on average by 0.61 mumol (0.15 mg)/mg of tiopronin administered. No changes in the efficacy of tiopronin over time were observed, and the frequency of adverse effects was acceptable. To evaluate the effects of tiopronin on the metabolism of cystine we calculated the total urinary excretion of cystine as the sum of free cystine and the amount of cystine corresponding to the cysteine content of the tiopronin-cysteine disulfide. At low doses of tiopronin there was an increase in urinary excretion of the mixed disulfide as well as of total cystine. Monitoring urinary cystine concentration is necessary to achieve adequate individualized doses of tiopronin. Assessment of the mixed tiopronin-cysteine disulfide and the urinary excretion of total cystine shows that tiopronin may interfere with cystine metabolism in a more complex way than through a simple disulfide exchange reaction with urinary cystine.

Adolescent↗
PubMed2004

Human platelets contain forms of factor V in disulfide-linkage with multimerin.

Factor V is an essential cofactor for blood coagulation that circulates in platelets and plasma. Unlike plasma factor V, platelet factor V is stored complexed with the polymeric alpha-granule protein multimerin. In analyses of human platelet factor V on nonreduced denaturing multimer gels, we identified that approximately 25% was variable in size and migrated larger than single chain factor V, the largest form in plasma. Upon reduction, the unusually large, variably-sized forms of platelet factor V liberated components that comigrated with other forms of platelet factor V, indicating that they contained factor V in interchain disulfide-linkages. With thrombin cleavage, factor Va heavy and light chain domains, but not B-domains,were liberated from the components linked by interchain disulfide bonds, indicating that the single cysteine in the B-domain at position 1085 was the site of disulfide linkage. Since unusually large factor V had a variable size and included forms larger than factor V dimers, the data suggested disulfide-linkage with another platelet protein, possibly multimerin. Immunoprecipitation experiments confirmed that unusually large factor V was associated with multimerin and it remained associated in 0.5 M salt. Moreover, platelets contained a subpopulation of multimerin polymers that resisted dissociation from factor V by denaturing detergent and comigrated with unusually large platelet factor V, before and after thrombin cleavage. The disulfide-linked complexes of multimerin and factor V in platelets, which are cleaved by thrombin to liberate factor Va, could be important for modulating the function of platelet factor V and its delivery onto activated platelets. Factor Va generation and function from unusually large platelet factor V is only speculative at this time.

Blood Platelets↗
PubMed2006

Differential effects of the loss of intrachain- versus interchain-disulfide bonds in the cystine-knot domain of von Willebrand factor on the clinical phenotype of von Willebrand disease.

Von Willebrand factor (VWF) contains a large number of cysteine residues, which all form disulfide bonds. Mutations of cysteines located in the cystine-knot (CK) domain of VWF have been identified in both qualitative type 2A (IID) and quantitative type 3 von Willebrand disease (VWD). Our objective was to test the hypothesis that the difference in phenotype is related to whether the mutated cysteine residue is involved in either interchain- or intrachain-disulfide-bond formation. The effects of three cysteine mutations which are all located in the CK-domain of VWF, C2773S (type 2A(IID)), C2739Y (type 3), and C2754W (type 3), were studied by transient expression in 293T cells. Cotransfection of wild-type (wt) and C2773S VWF constructs reproduced the plasma phenotype of heterozygous type 2A(IID) patients, with normal to high levels of VWF antigen (VWF:Ag), absence of high-molecular-weight multimers, and the presence of intervening bands between the normal multimers. In contrast, single transfections of C2739Y or C2754W resulted in a quantitative VWF defect with low VWF:Ag levels, and co-transfections of wt and mutant constructs resulted in a 50% reduction of VWF:Ag and only a minor effect on VWF multimerization. We demonstrated N-terminal dimerization of VWF-C2773S and both N- and C-terminal dimerization of VWF-C2754W. Our data suggest that loss of a single disulfide bond in the CK-domain of VWF leads to a recessive, quantitative VWF deficiency if an intrachain-disulfide bond is involved, and to a dominant-negative, qualitative defect of VWF if an interchain-disulfide bond is involved.

ADAM Proteins↗
PubMed2002

Sustained integrin ligation involves extracellular free sulfhydryls and enzymatically catalyzed disulfide exchange.

Studies have suggested a pivotal role for free sulfhydryls in platelet integrin function, and enzyme-mediated reduction of disulfide bonds on platelets has been implicated. The platelet fibrinogen receptor alpha(IIb)beta(3) is the best-studied platelet integrin and serves as a model system for studying the structure-function relation in this family of adhesion receptors. The demonstration of free sulfhydryls on the exofacial domain of purified alpha(IIb)beta(3), specifically in its activated conformation, prompted us to explore the potential for activation-dependent, enzymatically catalyzed thiol expression on intact platelets and the possible role of surface-associated protein disulfide isomerase (PDI) in alpha(IIb)beta(3) ligation. Using the membrane-impermeant sulfhydryl blocker para-chloromercuriphenyl sulfonate, the inhibitor of disulfide exchange bacitracin, and the monoclonal anti-PDI antibody RL90, we examined fibrinogen binding to alpha(IIb)beta(3) as well as ligation-induced allosteric changes in the conformation of alpha(IIb)beta(3). We sought to distinguish the possible involvement of disulfide exchange in agonist-induced platelet stimulation from its role in integrin ligation. Analysis of the role of free thiols in platelet aggregation suggested a thiol-independent initial ligation followed by a thiol-dependent stabilization of binding. Flow cytometric analysis showed that sustained binding of fibrinogen, as well as expression of ligand-induced binding site epitopes and ligand-bound conformation, depended on free thiols and disulfide exchange. Expression of P-selectin was minimally affected, even with complete inhibition of alpha(IIb)beta(3) function. These data indicate that although agonist-induced platelet stimulation is independent of ecto-sulfhydryls, engagement of integrin alpha(IIb)beta(3) on the intact platelet depends totally on their enzymatically catalyzed surface expression.

Antibodies, Monoclonal↗
PubMed2006

Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta subunits in the resting platelet.

It is widely accepted that glycoprotein (GP) Ib contains one Ibalpha and one Ibbeta subunit that are connected by a disulfide bond. It is unclear which Cys residue in Ibalpha, C484 or C485, forms the disulfide bond with Ibbeta. Using mutagenesis studies in transfected Chinese hamster ovary (CHO) cells, we found that both C484 and C485 formed a disulfide bond with C122 in Ibbeta. In the context of isolated peptides containing the Ibalpha or Ibbeta transmembrane domain and nearby Cys residue, C484 and C485 in the Ibalpha peptide were both capable of forming a disulfide bond with the Ibbeta peptide. Furthermore, coimmunoprecipitation of epitope-tagged subunits showed that at least 2 Ibbeta subunits but only 1 Ibalpha and 1 IX subunit were present in the GP Ib-IX complex. Finally, the size difference between GP Ib from transfected CHO cells and human platelets was attributed to a combination of sequence polymorphism and glycosylation difference in Ibalpha, not the number of Ibbeta subunits therein. Overall, these results demonstrate that Ibalpha is covalently connected to 2 Ibbeta subunits in the resting platelet, necessitating revision of the subunit stoichiometry of the GP Ib-IX-V complex. The alphabeta2 composition in GP Ib may provide the basis for possible disulfide rearrangement in the receptor complex.

Animals↗
PubMed1983

Role of disulfide bonds in human growth hormone binding and dissociation in isolated rat hepatocytes and liver plasma membranes.

The role of disulfide bonds and sulfhydryl groups in rat hepatocytes and rat liver plasma membranes in the binding of human GH (hGH) has been studied. Since hGH binding involves uptake and irreversible binding, the effect of disulfide reducing agents [dithiothreitol (DTT) and 2-mercaptoethanol (ME)] and an alkylating agent [N-ethylmaleimide (NEM)] on the time course of binding and displacement of [125I]hGH was determined in the hepatocytes and membranes. The time course of binding and displacement of [125I]hGH was similar in membranes and cells, indicating that the irreversible nature of hGH binding is not dependent upon an intact cellular structure. Both 1% ME and 10 mM DTT prevented further binding of [125I]hGH when added at 60 min of the 300-min binding incubation for both hepatocytes and plasma membranes. The ME caused some initial dissociation of bound [125I]hGH, with subsequent binding to levels that were present when the ME was added. Only ME caused an increase in nonspecific binding with the plasma membranes. Both ME and DTT caused an increase in displacement of [125I]hGH in the presence of excess unlabeled hGH. The amount of [125I]hGH remaining bound in the presence of DTT and unlabeled hGH approached nonspecific levels by 240 min of incubation. NEM caused an increase in the total [125I]hGH bound, but this was apparently due to increased nonspecific binding in the presence of NEM. The effect of the reducers on binding was not secondary to an effect on hGH, since the disulfides of [125I]hGH were not reduced under the conditions of binding with either ME or DTT. The effect of the ME or DTT on binding could be reversed or prevented by subsequent or simultaneous addition of an oxidizer such as NAD or oxidized glutathione. The data indicate that disulfide bonds in the membranes are intimately involved in the maintenance of a receptor structure necessary for hGH binding. The disruption of the disulfides also results in increased dissociation and displacement of the bound [125I]hGH, indicating a possible role in the irreversible nature of hGH binding. This represents a partial delineation of the hGH binding process.

Animals↗
PubMed2000

Cleavage of S-S bond by nitric oxide (NO) in the presence of oxygen: a disproportionation reaction of two disulfides.

Disulfide bond was cleaved by a catalytic amount of nitric oxide in the presence of oxygen, which was confirmed by experiments employing two symmetrical disulfides. The reaction resulted in the formation of unsymmetrical disulfides in nearly 50% yields. The steric hindrance of alkyl disulfide slowed the reaction rate, and an electron-donating group on the aryl disulfide promoted the reaction. The substituent and S-nitrosothiol effects suggested that the reaction was initialized with an oxidative process by NO+.

Disulfides↗
PubMed1982

Early and late cathepsin D-derived fragments of fibronectin containing the C-terminal interchain disulfide cross-link.

Fibronectin consists of two very similar subunits connected by disulfide bonds close to their C-terminal ends. After short digestion with cathepsin D a fragment containing an intact subunit linked to a C-terminal piece of the other chain was isolated. Both possible combinations were realized. The remnant chain, removed by reduction, had a relative molecular mass (Mr) of 65000 or 75000, respectively, whether it originated from the shorter or the longer fibronectin subunit. After prolonged cathepsin D digestion another disulfide-linked fragment of Mr 90000 containing peptide chains of Mr 65000 and Mr 36000 was found. The same fragment also formed during prolonged digestion of a previously described cathepsin D-derived heparin-binding piece of Mr 140000 which consisted of disulfide-linked chains of Mr 65000 and Mr 75000. The cut-off material emerged as a mixture of two similar heparin binding peptides of Mr 35000 and Mr 37000. The residual disulfide-linked peptide of Mr 90000 was retained by heparin-Sepharose, too, indicating that the non-degraded chain of Mr 65000 also contained a heparin-binding site. Plasminolysis of the Mr 140000 fragment first liberated the two individual chains and subsequently cleaved the longer one into two domains of nearly equal size. A rather basic one (pI 8.4-8.8) with low cystine content bound to heparin-Sepharose, while the other cystine-rich and more acidic domain (pI 5.0-5.8) was not retained. The shorter peptide chain, also showing affinity to heparin, was attacked by plasmin rather slowly. It, however, also appeared to be composed of two differently charged regions as it had an isoelectric point in the neutral range (pI 6.4-6.8) in spite of its heparin-binding properties. In the longer chain the heparin-binding domain was located in a distal position to the C-terminal disulfide link. The same is assumed for the shorter chain by reason of homology.

Amino Acids↗
PubMed1992

Intra- and interchain disulfide bridges of the human J chain in secretory immunoglobulin A.

All intra J chain disulfide bridges of human sIgA, the disulfide bonds between the J chain and the two IgA monomers, and one inter IgA monomer disulfide bridge were determined. sIgA was isolated from colostrum of healthy women and digested with IgA1-specific protease followed by cyanogen bromide cleavage. This procedure generated fragments of 140 kDa, 60 kDa, and 28 kDa. The 28-kDa polypeptide comprised the complete J chain covalently bound to two alpha 1 chain octapeptides derived from the C-termini of two alpha 1 chains. The 28-kDa fragment was digested with trypsin. The resulting peptides were purified by RP-HPLC, and subsequently characterized by amino-acid analysis, mass spectrometry, and gas phase sequencing. These data unequivocally show that the J chain cysteines C1-C6, C4-C5, and C7-C8 form intra chain disulfide bridges. The second (C2) and the third (C3) J chain cysteines are disulfide linked to two alpha chain cysteines (C17) joining the two IgA monomers of sIgA tail to tail. The remaining two alpha chains of the two monomers are directly bound to each other via their ultimate cysteines (C17-C17). A new model for the J chain in sIgA is presented.

Amino Acid Sequence↗
PubMed1976

Systolic time intervals as a measure of left ventricular function in viscose rayon workers exposed to carbon disulfide.

In a group of viscose rayon workers exposed to carbon disulfide the systolic time intervals were calculated. They were determined from the simultaneous recording of an ECG, a phonocardiogram, and arterial pulse tracings. Results indicate a shortened left ventricular ejection time (lvet) and a prolonged isovolumetric contraction time (ICT), together with an increase in the ratio of ICT to LVET. These alterations, which occurred in the absence of any clinical signs or symptoms of heart disease, are interpreted as a consequence of an impaired left ventricular contractility, comparable to mild coronary dysfunction. Literature data support the hypothesis that the biochemical mechanisms involved in the effect of carbon disulfide on myocardial cells are (a) an interference with energy metabolism from the inadequate availability of thiamine and nicotinamide or a direct inhibition of cytochrome or (b) an interference with catecholamine metabolism and defective hormonal control of the energy utilization process. Impaired left ventricular function in rayon viscose workers exposed to carbon disulfide represents an early and highly sensitive sign of carbon disulfide intoxication, and the use of systolic time intervals as a noninvasive measure of myocardial performance may be a useful method for monitoring carbon disulfide exposed people.

Air Pollutants↗
PubMed1975

Electrophysiological studies on rabbits in long-term exposure to carbon disulfide.

Electroneuromyography was performed as part of a multidemensional study of experimental carbon disulfide poisoning of rabbits. Ten rabbits were exposed by inhalation of 750 ppm of carbon disulfide for 6 hours a day, 5 days a week for 10 weeks. A slowing of the motor conduction velocity of the sciatic nerve was clearly observable during the course of exposure. This slowing preceded clinical paralysis, which became severe in the hind limbs within 9 weeks. Although the amplitude of the motor response to stimulation diminished markedly towards the end of the exposure period, a response of about 2 mV was always elicitable. Definite fibrillations could be noted in the gastrocnemius muscle of the rabbits after exposure for 9 weeks. In the two rabbits allowed to recover, the fibrillations continued for up to 2 months after the cessation of the carbon disulfide exposure. As the paralysis was very severe, even though the nervous conductivity was rather well preserved, it was assumed that a lesion at the spinal cord level was combined with neuropathy. These experimental findings from rabbits agreed well with results from clinical studies of workers occupationally exposed to carbon disulfide. Some similarities, but also differences, were observable between neurophysiological findings in carbon disulfide and other forms of experimental toxic neuropathy.

Animals↗
PubMed1999

Determination of disulfide bonds in gamma-46 gliadin.

The disulfide bonds in gamma-46 gliadin were identified: Cys173--Cys192, Cys212--Cys291, Cys165--Cys199 (or Cys200), Cys283--Cys200 (or Cys199). The disulfide-containing peptides were obtained by limited hydrolysis of the intact protein with chymotrypsin at an enzyme/substrate ratio of 1:1000 at 20 degrees C for 22 h with subsequent digestion of disulfide-containing fragments with trypsin and chymotrypsin. The locations of disulfide bonds were determined by sequencing disulfide-containing fractions and constituent peptides and comparison of the obtained sequences with the partial amino acid sequence of gamma-46 gliadin determined earlier.

Amino Acid Sequence↗
PubMed1999

Interprotein disulfide bonds formed during isolation process tighten the structure of the postsynaptic density.

Postsynaptic densities (PSDs) isolated by biochemical means consist of a complex mixture of proteins that tightly bond to each other. The purpose of this report is to study whether the numerous interprotein disulfides found in the isolated PSDs contribute to the tight structure of the PSDs and whether these interprotein disulfides exist in vivo. PSDs were isolated from pig cerebral cortex by conventional methods except that iodoacetic acid (IAA) was added to all solutions to curtail the formation of disulfides during the isolation process. The PSDs thus isolated were fragmented easily by treatment with chaotropic reagents or ionic detergents, whereas the PSDs isolated in IAA-free solutions were resistant to these treatments. Electron microscopy revealed that the PSDs isolated in IAA-containing solutions were more fragmented than those isolated in IAA-free solutions. Furthermore, the PSD sample isolated in IAA-free solutions contained very large disulfide-linked aggregates that were virtually absent from the PSDs isolated in IAA-containing solutions. Our results suggest that the exceptionally tight structure of the PSDs isolated by conventional methods is due largely to the new disulfides formed during the isolation process and that the PSD proteins under in vivo conditions are held together primarily by noncovalent interactions.

Animals↗
PubMed1977

Reaction of cardiac myosin with a purine disulfide analog of adenosine triphosphate. I. Kinetics of inactivation and binding of adenylyl imidodiphosphate.

Bovine cardiac myosin ATPase activity was rapidly inactivated by the purine disulfide analog of ATP,6,6'-dithiobis(inosinyl imidodiphosphate). Kinetic investigations showed that this analog acted as a site-specific reagent at 0 degrees with a Ki of 130 muM and a half-life of 8.2 min at saturating inhibitor concentrations. Concentrations (50 to 500 muM) of ATP, adenyl-5'-yl imidodiphosphate (AMP-PNP), or ADP that saturated the active site caused an enhancement in the rate of inactivation, indicating the purine disulfide analog was not reacting at the active site. Under these conditions saturation kinetic data were still observed with Ki values remaining unchanged (120 muM) but with the half-life of inactivation decreasing to 6.0 min (ATP) and 4.6 min (AMP-PNP) at saturating inhibitor concentrations. At concentrations greater than 0.5 mM ATP, AMP-PNP, or ADP there was a decrease in the rate of inactivation, implying protection by these nucleotides. However, saturation kinetics of inactivation could no longer be demonstrated, implying a change in the mechanism of inactivation. A comparison of the inactivation of the Mg2+, Ca2+, and EDTA-ATPase activities of cardiac myosin after modification by the purine disulfide analog showed that the Mg2+- and Ca2+ATPase activities plateaued at approximately 60% and 40%, respectively, while the EDTA-ATPase activity continued to decrease to below 10%. This evidence supports the suggestion that the purine disulfide analog was not reacting at the active site. Equilibrium dialysis experiments were used to measure the binding of [8-3H]AMP-PNP to native cardiac myosin, the thiopurine nucleotide-modified myosin, and the derivative formed by displacing the thiopurine nucleotide by cyanide (thiocyanato-myosin). Native myosin bound a total of 2.1 mol of AMP-PNP with a binding constant of 6.0 X 10(6) M-1. There was a 15 to 40% decrease in the number of AMP-PNP binding sites in the enzyme derivatives, but the active sites appeared not to be blocked since the association constants remained essentially unchanged (KA=3.9 X 10(6) M-1 for thiopurine nucleotide-myosin and 12.0 X 10(6) M-1 for thiocyanato-myosin). The kinetic studies and the binding experiments indicate that the purine disulfide analog reacts at a specific site other than the active site but do not offer support to earlier suggestions from skeletal myosin studies that this site is a possible ATP control site.

Adenosine Triphosphatases↗
PubMed2003

Optimizing the MALDI-TOF-MS observation of peptides containing disulfide bonds.

The observation of peaks corresponding to both disulfide-bonded and reduced peptides in matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectra of disulfides could suggest that the samples are either mixtures prior to analysis or that the measurement process has converted single compounds into mixtures. This is an important distinction when characterizing potentially disulfide-bonded peptides obtained from proteolyzed proteins or from oxidized synthetic peptides. It is well documented that disulfides can undergo in-source decay (ISD) when using a 337-nm laser. However, the mixed matrix 2-(4-hydroxyphenylazo)benzoic acid:alpha-cyano-4-hydroxycinnamic acid (1:10) not only suppresses the ISD reduction of disulfides to thiols but allows the same low threshold laser power generally used with alpha-cyano-4-hydroxycinnamic acid to be applied.

Benzoates↗
PubMed1992

Characterization of disulfide-linked heterodimers containing apolipoprotein D in human plasma lipoproteins.

Human plasma apolipoprotein (apo) D is a glycoprotein with an apparent molecular weight of 29,000 M(r). It is present, mainly, in high density lipoproteins (HDL) and very high density lipoproteins (VHDL). Western blot analysis of HDL and VHDL using rabbit antibodies to human apoD revealed major immunoreactive bands at 29,000 and 38,000 M(r), with minor bands ranging from 50,000 to and 80,000 M(r). Only the 29,000 M(r) band corresponding to apoD remained when the electrophoresis was conducted under reducing conditions, demonstrating that apoD is cross-linked to other proteins via disulfide bonds. The broad pattern of immunoreactivity was also observed under nonreducing conditions when the blood was collected into a solution of sulfhydryl-trapping reagents, or when these reagents were added to the isolated lipoproteins. These results indicated that the disulfide bonds were not the result of disulfide exchange during the experimental procedures. On the basis of amino acid sequencing and reactions to antibodies, the 38,000 M(r) band was identified as an apoD-apoA-II heterodimer. The apoD-apoA-II was also demonstrated in plasma. In both HDL and plasma, the apoD-apoA-II heterodimer constituted the major form of apoD. Disulfide-linked heterodimers of apoD and apoB-100 were also found in low and very low density lipoproteins, and in whole plasma. It is concluded that a fraction of human apoD, like other cysteine-containing apolipoproteins, exists as a disulfide-linked heterodimer with other apolipoproteins in all major human lipoprotein fractions.

Amino Acid Sequence↗
PubMed2004

Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent.

Thiamine tetrahydrofurfuryl disulfide (TTFD) is the synthetic counterpart of allithiamine, occurring naturally in garlic. Allithiamine was discovered in Japan in 1951. Its extensive research was reported by a group known as the Vitamin B Research Committee of Japan, and given this name because of its existence in the bulbs of many of the allium species of plants. It was found to be a disulfide derivative of thiamine, produced as a result of enzymatic action on the thiamine molecule in garlic bulbs when the bulb is cut or crushed. Subsequent experimental work in both animals and human subjects revealed that its metabolic effect was much more powerful than the thiamine from which it was derived. Japanese investigators created a number of synthetic forms and investigated their use in a number of human disease conditions. Although some derivatives have been synthesized without a disulfide bond in the molecule, these investigators emphasized that the disulfide was an extremely important part of its biologic action and TTFD is the most modern of the disulfide derivatives. Because at least part of its beneficial effects are the same as water soluble thiamine salts, this review deals first with the clinical uses of thiamine (vitamin B1) in medicine.

Disulfides↗