Decarboxylation Reactions

Many pathways to natural products involve steps which remove portions of the carbon skeleton. Although two or more carbon atoms may be cleaved off via the reverse aldol or reverse Claisen reactions mentioned above, by far the most common degradative modification is loss of one carbon atom by a decarboxylation reaction. Decarboxy-lation is a particular feature of the biosynthetic utilization of amino acids, and it has already been indicated that several of the basic building blocks, e.g. C6C2N, indole.C2N, are derived from an amino acid via loss of the carboxyl group. This decarboxylation of amino acids is also a pyridoxal phosphate-dependent reaction (compare transamination) and is represented as in Figure 2.15(a). This similarly depends on Schiff base formation and shares features of the transamination sequence of Figure 2.14. Decarboxylation is facilitated in the same way as loss of the a-hydrogen was facilitated for the transamination sequence. After protonation of the original a-carbon, the amine is released from the coenzyme by hydrolysis of the Schiff base function.

P-Keto acids are thermally labile and rapidly decarboxylated in vitro via a cyclic mechanism which proceeds through the enol form of the final ketone [Figure 2.15(b)]. Similar reactions are found in nature, though whether cyclic processes are necessary is not clear. ortho-Phenolic acids also decarboxylate readily in vitro and in vivo, and it is again possible to invoke a cyclic P-keto acid tau-tomer of the substrate. The corresponding decar-boxylation of para-phenolic acids cannot have a cyclic transition state, but the carbonyl group in the proposed keto tautomer activates the system for decarboxylation. The acetate pathway frequently yields structures containing phenol and carboxylic acid functions, and decarboxylation reactions may thus feature as further modifications. Although the carboxyl group may originate by hydrolysis of the

Transamination reductive amination

HO2C 2-oxoglutaric acid glutamate dehydrogenase

HO2C

1NH2

HO2C

HO2C

glutamic acid L-Glu

HO2C

transaminase O

HO2C

HO2C

glutamic acid keto acid

H NH2 CHO

N^CH3

pyridoxal P (PLP)

HO2C

2-oxoglutaric acid amino acid formation of imine from aldehyde and amino acid

N CH3 pyridoxamine P

NH2 OH

N CH3 pyridoxamine P

hydrolysis of imine to keto acid and amine a-hydrogen is now acidic PO

^co2h hM

I N "CH3 VH® aldimine

I N "CH3 VH® aldimine

Acetyl Coa Thioester Hydrolysis

Figure 2.14

N CH3 ketimine

Figure 2.14

thioester portion of the acetyl-CoA precursor, there are also occasions when a methyl group can be sequentially oxidized to a carboxyl, which then subsequently suffers decarboxylation.

Decarboxylation of a-keto acids is a feature of primary metabolism, e.g. pyruvic acid ^ acetaldehyde in glycolysis, and pyruvic acid ^ acetyl-CoA, an example of overall oxidative decarboxylation prior to entry of acetyl-CoA

into the Krebs cycle. Both types of reaction depend upon thiamine diphosphate (TPP). TPP is a coenzyme containing a thiazole ring, which has an acidic hydrogen and is thus capable of yielding the carbanion. This acts as a nucle-ophile towards carbonyl groups. Decarboxylation of pyruvic acid to acetaldehyde is depicted as in Figure 2.15(c), which process also regenerates the carbanion. In the oxidation step of oxidative

Decarboxylation reactions (a) amino acids

H NH2

NH2 CHO

NH2 CHO

formation of imine hydrolysis of imine to aldehyde and amine

6-membered H-bonded system

R CH2

P-keto acid

CO2H

phenolic acid (i.e. enol tautomer)

keto-enol tautomerism

R'C*CH2

intermediate enol

6-membered H-bonded system O-.

H ii

keto tautomer = P-keto acid

keto tautomer keto tautomer

thiamine diphosphate (TPP)

h acidic hydrogen

TPP anion regenerated

O 11

h3c h

lipoic acid

nucleophilic attack of carbanion on to carbonyl: aldol-type reaction ^q

reverse aldol-type reaction

TPP anion

tautomerism

lminium ion decarboxylation of $-iminium acid

H3C H enamine-imine h3C

lipoic acid

H3C^OH p R3

N! ^ S enzyme-bound lipoic acid

enamine enamine attacks S of lipoic acid fragment with S-S bond fission H

oj hvr3

C HS XS

acetyl group displaced by coenzyme A

HSCoA

regeneration of TPP carbanion leaves acetyl group attached to dihydrolipoic acid

\y enzyme-bound lipoic acid

H3C SCoA

acetyl-CoA

HSv!

original lipoic acid fragment has become reduced to dithiol; oxidation regenerates the enzyme-bound lipoic acid

Figure 2.15 (continued)

decarboxylation, the enzyme-bound disulphide-containing coenzyme lipoic acid is also involved. The intermediate enamine in Figure 2.15(c), instead of accepting a proton, is used to attack a sulphur in the lipoic acid moiety with subsequent S—S bond fission, thereby effectively reducing the lipoic acid fragment. This allows regeneration of the TPP carbanion, and the acetyl group is bound to the dihydrolipoic acid. This acetyl group is then released as acetyl-CoA by displacement with the thiol coenzyme A. The bound dihydrolipoic acid fragment is then reoxidized to restore its function. An exactly equivalent reaction is encountered in the Krebs cycle in the conversion of 2-oxoglutaric acid into succinyl-CoA.

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