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Mecanismos de Bioquímica · Biomolecules

Carboidratos: estrutura, anômeros e glicosídeos

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O que você vai aprender

  • Read Fischer, Haworth and chair drawings of monosaccharides and assign D/L, α/β, pyranose/furanose, epimer and enantiomer relationships.
  • Draw cyclic hemiacetal formation and acid- or base-catalysed mutarotation, and calculate anomer composition from optical rotation.
  • Draw glycoside formation and hydrolysis through oxocarbenium ions, identify reducing and non-reducing sugars, and explain how a neighbouring acyl group controls anomeric configuration.
  • Distinguish inverting from retaining glycosidases by their single- or double-displacement mechanisms and predict the anomer each releases.
  • Predict the products of reduction, oxidation, base-catalysed epimerisation, Kiliani–Fischer chain extension and protein glycation at the open-chain carbonyl group.

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Aldoses, ketoses and the D/L label

A monosaccharide is a polyhydroxy aldehyde (an aldose) or a polyhydroxy ketone (a ketose); glucose is an aldohexose and fructose a ketohexose. In a Fischer projection the carbon chain runs vertically with C1 at the top, horizontal bonds point toward the viewer and vertical bonds away. The D/L label refers only to the stereocentre farthest from the carbonyl group (C5 in a hexose): if its OH points right, as in D-glyceraldehyde, the sugar is D. D and L say nothing about the sign of optical rotation: D-glucose is dextrorotatory but D-fructose is strongly levorotatory. An open-chain aldohexose has four stereocentres (C2–C5) and therefore 2⁴ = 16 stereoisomers, eight D and eight L; a 2-ketohexose has three (C3–C5) and 2³ = 8. Enantiomers differ at every stereocentre (D- and L-glucose). Diastereomers that differ at exactly one stereocentre are epimers: D-mannose is the C2 epimer and D-galactose the C4 epimer of D-glucose, while D-mannose and D-galactose differ at two centres and are diastereomers but not epimers.

Rings: pyranoses, furanoses and anomers

An OH group of a sugar adds to its own carbonyl group to give a cyclic hemiacetal (from an aldose) or hemiketal (from a ketose). In glucose the C5 oxygen attacks C1 and closes a six-membered pyranose ring; in fructose the C5 oxygen attacks C2 to give a five-membered furanose, the ring found in sucrose and fructose 6-phosphate, although free fructose in water is mostly the pyranose formed by the C6 oxygen. The former carbonyl carbon is the anomeric carbon, and it is a new stereocentre, so each ring exists as two anomers. In the standard Haworth drawing of a D-sugar the CH₂OH group points up; every OH on the right of the Fischer projection points down. The α anomer has its anomeric OH on the opposite face to that CH₂OH (down), the β anomer on the same face (up). In the ⁴C₁ chair of β-D-glucopyranose every substituent, including the anomeric OH, is equatorial; in the α anomer the anomeric OH is axial.

Mutarotation

Pure α-D-glucopyranose has a specific rotation of +112.2° and pure β-D-glucopyranose +18.7°. Dissolved in water, either one drifts to +52.7°, because the hemiacetal reopens to the free aldehyde and recloses on either face. Linear mixing gives the equilibrium composition: fraction β = (112.2 − 52.7)/(112.2 − 18.7) ≈ 0.64, so about 36 % α and 64 % β, with well under 0.1 % open-chain aldehyde. Acid catalyses ring opening by protonating the ring oxygen; base catalyses it by removing the anomeric OH proton, after which the alkoxide expels the ring oxygen as an alkoxide. The anomeric effect, an interaction of a ring-oxygen lone pair with the C1–O σ* orbital, favours an axial electronegative group at C1, but in water it is weaker than the steric preference for the all-equatorial β anomer, so β dominates for glucose.

Glycosides, disaccharides and reducing sugars

Replacing the anomeric OH by OR turns the hemiacetal into an acetal, a glycoside. In Fischer glycosidation (methanol and HCl) the protonated anomeric OH leaves as water while the ring oxygen lone pair forms an oxocarbenium ion; methanol adds to either face, and after equilibration methyl α-D-glucopyranoside predominates. Aqueous acid reverses the process through the same cation. A glycoside cannot open to an aldehyde, so it neither mutarotates nor reduces Tollens' or Benedict's reagent; a sugar with a free hemiacetal (a reducing end) does both. Maltose is Glcα(1→4)Glc, cellobiose Glcβ(1→4)Glc and lactose Galβ(1→4)Glc, and all three are reducing. Sucrose (shown, with lactose) joins C1 of glucose to C2 of fructose, so neither anomeric carbon is free and it is non-reducing. Acid cleaves sucrose on the fructose side through a tertiary fructofuranosyl oxocarbenium ion, giving invert sugar, an equimolar glucose–fructose mixture whose rotation is negative. In synthesis, a 2-O-acetyl group captures the glycosyl cation as a cis-fused dioxolenium ion, so the alcohol can only add to the opposite face and gives the 1,2-trans glycoside.

Glycosidases: inverting and retaining

Glycosidases use two carboxyl groups. In an inverting enzyme, such as glucoamylase, the two carboxyl groups sit about 10 Å apart: one carboxylate deprotonates a water molecule that attacks the anomeric carbon from the face opposite the leaving group, while the other carboxylic acid protonates the departing glycosidic oxygen. One displacement gives one inversion, so glucoamylase cuts α(1→4) links and releases β-D-glucose. In a retaining enzyme, such as β-galactosidase, the carboxyl groups are about 5.5 Å apart: one carboxylate attacks C1 to form a covalent glycosyl-enzyme ester while the other protonates the leaving group, then that second carboxylate activates water to attack C1 again. Two inversions make a net retention. Both steps pass through oxocarbenium-like transition states. A 2-fluoro substituent slows both steps, and with a good leaving group at C1 the covalent intermediate accumulates and can be detected. Because a retaining enzyme holds the sugar as an ester, an alcohol can replace water: β-galactosidase uses glucose as the acceptor to make allolactose. Cells build glycosidic bonds from activated donors with good anomeric leaving groups, such as UDP-glucose for glycogen synthase.

Reactions at the open-chain carbonyl

The small open-chain fraction reacts like any aldehyde, and the ring equilibrium refills it. NaBH₄ reduces an aldose to an alditol: D-glucose gives optically active D-glucitol (sorbitol), but D-galactose gives galactitol (shown), which has a mirror plane and is meso. Bromine water oxidises the aldehyde to an aldonic acid (D-gluconic acid); nitric acid oxidises both ends to an aldaric acid. Dilute base removes the C2 proton next to the aldehyde to give an enediolate; reprotonation on either face interconverts D-glucose and D-mannose, and protonation at C1 gives D-fructose. In the Kiliani–Fischer synthesis cyanide adds to C1 of an aldose on both faces, so D-arabinose gives two cyanohydrins that lead to D-glucose and D-mannose. In the body glucose condenses with protein amino groups to an imine, which tautomerises through an enaminol to a stable 1-amino-1-deoxyketose (the Amadori product); glycated haemoglobin, HbA1c, records average blood glucose over the previous two to three months.

What to carry forward

Find the anomeric carbon first. If it carries OH, the sugar is a hemiacetal that opens, mutarotates, reduces metal ions and reacts as an aldehyde or ketone; if it carries OR, it is a glycoside that only acid or an enzyme opens, through an oxocarbenium ion or an oxocarbenium-like transition state. Count inversions at C1 to predict the anomer a glycosidase releases: one for an inverting enzyme, two (net retention) for a retaining one. In synthesis, a participating 2-O-acyl group blocks one face of the glycosyl cation, so the alcohol adds trans to it and gives the 1,2-trans glycoside.

Problemas de prática (40)

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Desenhe o mecanismo 12

Reactions of the open-chain carbonyl

  • Glycation: Amadori rearrangement of a glucose–amine Schiff baseDraw the acid–base-catalysed tautomerisation of the imine formed from D-glucose and an amine, through the enaminol, to the 1-amino-1-deoxy-D-fructose (Amadori product).
  • Base-catalysed epimerisation of D-glucose to D-mannoseDraw how hydroxide removes the C2 proton of open-chain D-glucose to form an enediolate and how reprotonation on the other face gives the C2 epimer D-mannose.
  • Kiliani–Fischer synthesis: cyanide adds to D-arabinoseDraw the addition of cyanide to the aldehyde carbon of D-arabinose and the protonation that gives the two epimeric cyanohydrins of the Kiliani–Fischer synthesis.
  • Sodium borohydride reduces D-galactose to galactitolDraw hydride transfer from borohydride to the open-chain aldehyde of D-galactose and protonation of the alkoxide by water, giving the alditol galactitol.

Glycosidases and glycosyl transfer

  • β-Galactosidase: double-displacement hydrolysis of lactoseDraw both displacements of a retaining glycosidase on lactose: formation of the covalent α-galactosyl-enzyme ester with release of glucose, then water attack at C1 that releases β-D-galactose with net retention.
  • Glucoamylase: inverting hydrolysis of maltoseDraw the single-displacement hydrolysis of maltose by an inverting glycosidase, in which a carboxylate activates water for backside attack at C1 while a carboxylic acid protonates the leaving oxygen, releasing β-D-glucose.

Glycosides and disaccharides

  • Fischer glycosidation: D-glucose to methyl α-D-glucopyranosideDraw the acid-catalysed conversion of glucopyranose into methyl α-D-glucopyranoside through the oxocarbenium ion, using protonated methanol as the acid and methanol as the base.
  • Koenigs–Knorr glycosylation: neighbouring-group participation gives the β-glucosideDraw silver-assisted ionisation of acetobromoglucose, capture of the oxocarbenium ion by the 2-O-acetyl group, and β-face opening of the acetoxonium ion by methanol to give the 1,2-trans methyl β-glucoside.
  • Acid hydrolysis of sucrose through a fructofuranosyl cationDraw the acid-catalysed hydrolysis of sucrose in which the fructose side of the glycosidic oxygen breaks, through a tertiary fructofuranosyl oxocarbenium ion, to give glucose and fructose.

Rings, anomers and mutarotation

  • D-Fructose closes to β-D-fructofuranoseDraw the acid-catalysed attack of the C5 hydroxyl group of open-chain D-fructose on its C2 ketone, giving the five-membered cyclic hemiketal β-D-fructofuranose.
  • Base-catalysed mutarotation of α-D-glucopyranoseDraw how catalytic hydroxide opens α-D-glucopyranose to the open-chain aldehyde and how the ring recloses on the other face to give β-D-glucopyranose.
  • D-Glucose closes to β-D-glucopyranoseDraw the acid-catalysed attack of the C5 hydroxyl group of open-chain D-glucose on its own aldehyde carbon, giving the six-membered cyclic hemiacetal β-D-glucopyranose.

Preveja o produto 5

Glycosidases and glycosyl transfer

  • When glucose replaces waterPredict the transglycosylation product formed when a sugar hydroxyl intercepts the covalent intermediate of a retaining glycosidase.

Reactions of the open-chain carbonyl

  • Bromine water and glucosePredict the product of selective oxidation of an aldose by bromine water.
  • Reduce D-glucosePredict the alditol formed when sodium borohydride reduces an aldose.

Glycosides and disaccharides

  • Neighbouring-group participation with a mannose donorPredict the anomer formed by neighbouring-group participation when the C2 substituent points to the other face, as in mannose.
  • Sequence the hydrolysis of a methyl glycosideOrder the elementary events of acid-catalysed glycoside hydrolysis through the oxocarbenium ion.

Classificar 7

Sugar structures: Fischer, Haworth and chairs

  • The C4 epimer of D-glucoseRecognise the C4 epimer of D-glucose among open-chain aldohexoses that differ at one or two centres.
  • Aldose or ketose?Classify an open-chain monosaccharide by its carbonyl type and carbon count.
  • Find L-glucoseIdentify the enantiomer of D-glucose and distinguish it from a sugar that differs only at C5.
  • Mannose and galactoseClassify the stereochemical relationship between two aldohexoses that differ at two stereocentres.

Rings, anomers and mutarotation

  • The anomeric carbon of fructofuranoseLocate the anomeric carbon and the ring size of a ketose in its furanose form.
  • Find α-D-glucopyranoseIdentify α-D-glucopyranose among its anomer, its enantiomer and its C2 epimer.

Glycosides and disaccharides

  • Which sugar is non-reducing?Identify a non-reducing disaccharide by checking whether either anomeric carbon carries a free OH.

Comparar 1

  • Count axial hydroxyl groupsRank D-pyranoses by the number of axial hydroxyl groups in the ⁴C₁ chair using their epimeric relationships to β-D-glucose.

Calcular 5

Rings, anomers and mutarotation

  • Free-energy difference between the glucose anomersConvert an equilibrium anomer ratio into a standard free-energy change.
  • Composition from mutarotationCalculate the equilibrium anomer composition of glucose from the specific rotations of the pure anomers and the equilibrium mixture.

Glycosides and disaccharides

  • Rotation of invert sugarCalculate the specific rotation of invert sugar from the specific rotations of its components.

Sugar structures: Fischer, Haworth and chairs

  • Stereoisomers of a 2-ketohexoseCount the stereoisomers of an open-chain 2-ketohexose from its number of stereocentres.
  • Stereoisomers of an aldohexopyranoseCount pyranose stereoisomers by including the anomeric carbon as a stereocentre.

Encontre o erro 1

  • Find the flaw in a glycosidase mechanismDiagnose a glycosidase mechanism whose number of displacements contradicts the observed anomeric outcome.

Interprete as evidências 3

Glycosidases and glycosyl transfer

  • Read the active-site geometryInfer the mechanism and the first-formed anomer of a glycosidase from the spacing of its catalytic carboxyl groups.

Sugar structures: Fischer, Haworth and chairs

  • Which OH groups point up?Convert a Fischer projection into a Haworth projection and place each ring hydroxyl group of a β-D-pyranose.

Glycosides and disaccharides

  • Read the glycosidic linkageName a disaccharide linkage by identifying the non-reducing residue, its anomeric configuration and the acceptor carbon.

Trabalhe de trás para frente 1

  • Which aldose gives a meso alditol?Work back from an optically inactive alditol to the aldohexose whose reduction gives it.

Planeje uma síntese 1

  • Choose the glycosyl donorChoose the activated sugar donor that a glycosyltransferase needs to make a glycosidic bond.

Explique por quê 4

Sugar structures: Fischer, Haworth and chairs

  • Why is levorotatory fructose called D?Explain that the D/L label describes the configuration at the stereocentre farthest from the carbonyl, not the sign of optical rotation.

Glycosidases and glycosyl transfer

  • Trapping the glycosyl-enzyme with a fluoro sugarExplain how a 2-deoxy-2-fluoroglycoside with a good leaving group traps the covalent intermediate of a retaining glycosidase.

Reactions of the open-chain carbonyl

  • Why glucose glycates proteins slowlyExplain the slow non-enzymatic glycation of proteins by glucose in terms of its ring–chain equilibrium.

Rings, anomers and mutarotation

  • Why β wins in waterExplain the equilibrium preference of D-glucose for the β anomer in terms of chair conformation and the anomeric effect.

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