Acetate

Acetate 147
Acetate 0%/0--OH3
HO
The term acetate (acetic acid; molecular weight 60) refers to both the carbonic acid
with a pungent odor and its salts. Figure 6.21 Acetate
Abbreviations
CoA coenzymeA
MC monocarboxylate transporter
Nutritional summary
Function: Acetate and particularly its conjugate with coenzyme A (acetyl-CoA) is a
critical intermediary metabolite for the utilization of carbohydrates, some amino acids
(lysine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan), fatty acids, and alcohol.
It can be used as a precursor for fatty acid and cholesterol synthesis. Acetate can also
be utilized as an energy fuel; its complete oxidation requires thiamin, riboflavin, niacin,
pantothenate, lipoate, ubiquinone, iron and magnesium.
Food sources: Only very small amounts are consumed with foods, mainly with vinegar,
fruits, and vegetables. Alcohol is converted completely into acetate. Several hundred
grams of acetyl-CoA are generated daily from the breakdown of carbohydrates, fat,
and protein.
Requirements: No dietary acetate intake is necessary. A beneficial effect of moderate
vinegar intake on blood sugar control and chronic inflammatory polyarthritis has been
claimed.
Excessive intake: High intakes of acetic acid (more than 10-20 g/day) may induce gas-
tric discomfort, alter pH balance (metabolic acidosis), cause the loss of bone minerals,
and increase the risk of dental erosion.
Copyright © 2003. Elsevier Science & Technology. All rights reserved.
Endogenous production
The metabolism of carbohydrates, amino acids, and fatty acids generates several hun-
dred grams of acetate per day, mainly as acetyl-CoA. Depending on intakes, significant
amounts of free actetate may also be generated from ethanol. Most is utilized within
the cells or tissues where the acetate or acetyl-CoA is generated, some is transported
to other tissues and utilized there.
Carbohydrates: The amount of acetate generated from glucose depends on the pro-
portion used for glycolysis (as opposed to the smaller fraction metabolized via the
pentose phosphate pathway) and the proportion used for the generation of oxaloac-
etate from pyruvate. Typically, about half a gram of acetate (as acetyl-CoA) is gener-
ated per gram of absorbed carbohydrate.
Amino acids: Acetyl-CoA is generated during the catabolism of isoleucine, leucine,
and threonine. Lysine and tryptophan each generate two acetyl-CoA molecules.
Metabolism of cysteine, alanine, and tryptophan generates pyruvate, which may be
Kohlmeier, Martin. Nutrient Metabolism : Structures, Functions, and Genetics, Elsevier Science & Technology, 2003. ProQuest Ebook Central,
http://ebookcentral.proquest.com/lib/upenn-ebooks/detail.action?docID=349544.
Created from upenn-ebooks on 2023-08-16 18:35:18.
148 Fatty Acids
0%
S/C --OH3
i
CH2
C,H2
NN
C=O
I
C,H2
CH2
NH
I
C--O
i
CN ON
I
HaC--C' --CH3
ON2
I
O
I
O-P=O
I NH
o
I
O-P=O
I
0
I
OH2
o ON
Figure 6.22 Acetyl-CoA is a critical intermediate of f'uel metabolism
converted into acetyl-CoA. Acetoacetate is generated by the catabolism of phenylala-

nine, tyrosine, and leucine (for the latter in addition to one mole of acetyl-CoA). The
acetoacetate can be activated by 3-oxoacid CoA-transferase (succinyl-CoA trans-

ferase, EC2.8.3.5) and then cleaved by acetyl-CoA C-acetyltransferase (thiolase,
EC2.3.1.9) to generate two moles of acetyl-CoA. A minor pathway of threonine
breakdown generates free acetate.
Fatty acids: One mole of acetyl-CoA is released with each cycle of fatty acid
beta-oxidation.
Alcohol: Ethanol is oxidized by various alcohol dehydrogenases (ECI.I.I.I) or the
microsomal ethanol oxidizing system (MEOS, unspecific monooxygenases of the
cytochrome P-450 family, ECI. 14.14.1) in conjunction with several types of aldehyde
dehydrogenases (EC1.2.1.3, EC1.2.1.4, and ECI.2.1.5) or acetaldehyde oxidase
(EC1.2.3.1). Ethanol metabolism occurs mainly in the liver, and most of the resulting
acetate is released into circulation (S ilet et al., 1999). One grarn of ethanol generates
about 1.3 g of acetate.
Fiber: Normal intestinal bacteria break down non-digestible carbohydrates and
release significant amounts of short-chain fatty acids including acetate.
Acetate 149
Glucose, Fructose, Galactose

;
Cysteine,
Tryptophan,
l
Alanine "~
0 0
II II
OH--C - - C --CH 3 OH - - C - - C H 3
H2
Tryptophan (2), Ethanol
Pyruvate
Lysine (2),
Leucine, (Threonine)
Isoleucine
0 O 0
II H2 //O II II
H3C - - C - - C - - C % P CoA--S--C--CH 3 9 OH - - C --CH 3
OH
Acetoacetate Acetyl CoA Acetate
Dietary fiber
(bacterial fermentation)
Figure 6.23 Endogenous sources ofacetate and its metabolites
Dietary sources
Acetate is ingested rnostly as vinegar (content typically 5-6%) and with pickle& mar-
inated or fermented foods. Typical intake is likely to be less than 1 g/day corresponding
to about one tablespoon ( 15 ml) of vinegar. Much smaller amounts are present in a wide
range of plant- and animal-derived foods as acetyI-CoA.
Intestinal absorption
Absorption of acetate from the srnail intestine (Watson et al., 1991; Tarnai eta/.,
1995), especially the jejunum, appears to proceed mainly via the proton/monocar-
boxylic acid cotransporter (MCT 1, SLC 16A 1), which is possibly present in the apical
and certainly in the basolateral enterocyte mernbrane (Garcia et al., 1994; Orsenigo
et al., 1999). Acetate can also be absorbed from colon and rectum, which is an irnpor-
tant site of bacterial production from dietary fiber (Wolever et al., 1995). MCTI and
possibly the SCFA /HCO3 antiporter contribute to this uptake (Stein et al., 2000).
The flow of protons across the lurninal rnembrane of the proximal colon via the
sodium/hydrogen exchanger also promotes the protonation of the acetate anion and
its subsequent passage into the enterocyte by non-ionic diffusion (von Engelhardt
et al., 1993).
15l) Fatty Acids
Transport and cellular uptake

Blood drculation: The proton/monocarboxylic acid cotransporter (MCT 1, SLC 16A 1)
is the main carrier for uptake of acetate, acetoacetate, and beta-hydroxybutyrate by
the liver and other critical tissues. The related carriers MCT2, MCT3, and MCT4 have
much more limited distribution.
Blood-brain barrier: Limited transport of acetate occurs across the epithelial cells of
the blood-brain barrier (Terasaki et al., 1991) via MCTI on both sides of the brain
capillary endothelial cell (Halestrap and Price, 1999). Interestingly, the foot processes
ofastroglial cell, which form part of the blood-brain barrier, express MCT2. This carrier
has much higher affinity for monocarboxylates than MCT 1 (Halestrap and Price, 1999).
Permeability of the blood-brain barrier increases greatly after several days of starvation
and in diabetes mellitus.
Metabolism
Acetate can be utilized by muscle and other peripheral tissues (Pouteau et al., 1996).
Complete oxidation of acetate requires thiamin, riboflavin, niacin, pantothenate, lipoate,
ubiquinone, iron, and magnesium.
First, free acetate must be conjugated to coenzyme A by acetate-CoA ligase (thio-
kinase; EC6.2.1.1 ). Most acetyI-CoA is utilized in mitochondria via the tricarboxylic
acid (Krebs) cycle. Citrate synthase (EC4.1.3.7)joins acetyl CoA to oxaloacetate. The
citrate from this reaction can then be metabolized further providing FADH, NADH,
and succinate for oxidative phosphorylation and ATP or GTP from succinyl CoA.
The production rate ofacetyl-CoA from fatty acid beta-oxidation in the liver with
prolonged fasting usually exceeds the capacity of the Krebs cycle. The coenzyme A
for continued beta-oxidation and other functions can be released through the produc-
tion of acetoacetate in three steps. The typical odor of a fasting individual is partially
related to exhaled acetone formed from acetoacetate. The conversion of acetoacetate
into beta-hydroxybutyrate taxes the body's acid-buffering capacity and may cause a drop
in blood pH (acidosis) in diabetics and similarly susceptible patients. None of these

events is related to dietary intake of acetate.
Ketogenesis takes place in the mitochondria where fatty acid catabolism generates
acetyl-CoA. AcetyI-CoA C-acetyltransferase (thiolase; EC2.3.1.9)joins two acetyl-
CoA molecules, and hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase;
EC4.1.3.5) adds another one. The mitochondrial isoform of HMG-CoA synthase is
genetically distinct from the cytosolic one, which generates the precursor for cholesterol
0% ATP+CoA H" +AMP+PPi O~NC

~ CH 3
c-cH3 < J' CoA-S
HO Acetate-CoA ligase
Acetate (magnesium) Acetyl-CoA
Figure 6.24 Acetatemust be activated before it can be utilized
Acetate 1S1
O
II
CoA--S - - C --CH 3
AcetyI-CoA
AcetyI-CoAC- /
acetyltransferase k
~ ""'~ CoA
O O
II II
CoA - - S ~ C - - C - - C - - C H 3
Acetoac~ H2
HMG-CoA r \
synthase F '~
CoA + H"
O OH ,, O
II I H2 I/" l
CoA - - S - - C - - C - - C - - C - - C \ /
H2 I OH /
OH3
3-Hydroxy-3-methylglutaryI-CoA
O
HMG-CoA CoA-- S - - C - - CH3
lyase AcetyI-CoA
NAD NADH H' CO2 O

HO LJ o
I H2 //0 , H2 \ ) ~_ H3C - - C - - O H 3
H3C - - C ~ C - - C \ -
H3C --C - - C - - O k non-enzymic
H OH 3-Hydroxybutyrate OH
13-hydroxybutyrate dehydrogenase Acetoacetate Acetone
Figure 6.25 Ketogenesisfrees up coenzymeA From acetyI-CoA

synthesis. HydroxymethylglutaryI-CoA lyase (HMG-CoA lyase, EC4.1.3.4) finally

generates acetoacetate by cleaving offacetyl-CoA from the HMG-CoA intermediate.
Spontaneous decarboxylation ofacetoacetate generates the dead-end product acetone.
Acetoacetate can also be reduced to beta-hydroxybutyrate by NADH-dependent
3-hydroxybutyrate dehydrogenase (ECI.I.I.30). This enzyme is allosterically acti-
vated by phosphatidyl choline. The reaction is fully reversible. Net flux depends on
substrate concentrations. Acetoacetate and beta-hydroxybutyrate (but not acetone)
can become a significant energy fuel for brain after several days of adaptation to star-
vation conditions.
Storage
Other than the rapidly metabolized amounts in cellular cytosol and body fluids,
acetate is not stored to a significant extent.
152 Fatty Acids
Excretion
Owing to its small molecular size, the renal glomerular membrane does not retain acetate.
Nearly all of the filtered acetate is recovered from the proximal renal tubular lumen.
Much of the uptake from the tubular lumen is mediated by the proton/monocar-
boxylic acid cotransporter 2 (MCT2, SLC16A2), which has a several-fold higher
affinity for its ligands than MCTI. Additional transporters, including MCTI, are likely
to play a role in acetate salvage from renal ultrafiltrate.
Regulation
AcetyI-CoA activates allosterically the biotin-dependent enzyme pyruvate carboxy-
lase (EC6.4.1.1) and thereby stimulates Krebs cycle throughput.
Dietary effects
Acetate inhibits lipolysis and replaces fat in the fuel mixture (Siler et al., 1999).
Acetic acid also lowers blood sugar levels (Ogawa et al., 2000), possibly by decreasing
the activities of sucrase, maltase, trehalase, and lactase (Ogawa et al., 2000), or by
delaying gastric emptying (Liljeberg and Bjorck, 1998).
Dietary vinegar was found to enhance intestinal calcium absorption in rats (Kishi
et al., 1999), but may at the same time increase urinary mineral loss and cause osteo-
porosis (Lhotta et al., 1998).
A combination of vinegar and honey has been claimed to be effective for the self-
treatment of chronic inflammatory polyarthritis (Carnara and Danao-Camara, 1999).
Drinking vinegar just once a week appears to be sufficient to increase the risk of
dental erosion (Jarvinen et ul., 1991 ).
References
Camara K, Danao-Calnara T. Awareness ol, use and perception of efficacy of alternative

therapies by patients with inflammatory arthropathies. Hawaii M e d J 1999:58:329-32
von Engelhardt W, Btirmester M, Hansen K, Becket G, Rechkemmer G. Effects of
amiloride and ouabain on short-chain thtty acid transport in guinea-pig large intestine.
J Phlwiol 1993:460:455 66
Garcia CK, Goldstein JL, Pathak RK, Anderson RG, Brown MS. Molecular characterization
of a lnembrane transporter for lactate, pyruvate, and other monocarboxylates: impli-
cations for the Cori cycle. ('ell 1994:76:865 73
Halcstrap AE Price NT. The proton-linked monocarboxylate transporter (MCT) family:
structure, function and regulation. Biochem .I 1999:343 Pt 2:281 99
,larvinen VK, Rytomaa II, Hcinonen OP. Risk factors in dental erosion..I Dent Res 1991:
70:942 -7
Kishi M, Fukaya M, TsukamotoY, Nagasawa T, Takehana K, Nishizawa N. Enhancing effect
of dietary vinegar on the intestinal absorption of calcium in ovariectomized rats. Biosci
Biotech Biochem 1999:63:905-10

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Acetate 147

converted into acetyl-CoA. Acetoacetate is generated by the catabolism of phenylala-

acetoacetate can be activated by 3-oxoacid CoA-transferase (succinyl-CoA trans-

Glucose, Fructose, Galactose

Figure 6.23 Endogenous sources ofacetate and its metabolites

Transport and cellular uptake

in blood pH (acidosis) in diabetics and similarly susceptible patients. None of these

0% ATP+CoA H" +AMP+PPi O~NC

Figure 6.24 Acetatemust be activated before it can be utilized

NAD NADH H' CO2 O

Figure 6.25 Ketogenesisfrees up coenzymeA From acetyI-CoA

synthesis. HydroxymethylglutaryI-CoA lyase (HMG-CoA lyase, EC4.1.3.4) finally

Camara K, Danao-Calnara T. Awareness ol, use and perception of efficacy of alternative

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