Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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This requires a new system of control which, in its

simplest form, is represented by cheap, physico-

chemical, time–temperature integrators for each lot

of product. A more suitable approach can be expected

from the application of microelectronic sensors

backed by a computer-assisted inventory manage-

ment system.

0148 Modern miniaturized, self-contained, time–tem-

perature data-logging sensors, with readable and/or

barcode readout, and computer-assisted processing of

the information, allow a system to control the flow-

time down the chain according to the remaining

quality life of the product.

0149 Monitoring product conditions During recent

years, a great number of devices for temperature

monitoring in conditioned distribution chains have

been developed, on mechanical, physicochemical,

microbiological, or electronic bases and with indicat-

ing or integrating functions, or both.

0150As it is impossible to keep track of the quality

development of every product by time–temperature

integration with one or even a handful of built-in

deterioration models, solutions can be found in the

classification of products and corresponding sensors

with direct indication, or sensors readable by a com-

puter-based system which compares the monitored

time–temperature load with stored keepability data,

and converts the result into information on the

remaining quality life expectation of the product.

0151For a wider use of such instruments, standardiza-

tion of sensors and information processing equipment

is necessary.

0152Simple time–temperature integrating devices can

monitor distribution chain operations for the general

purposes of quality management. But even highly

sophisticated monitoring systems remain in need of

expert supervision, because of the general rule that

the sensor is not identical with the product.

Effects of Scale

0153Costs per unit of storage and transport rise ap-

proximately with the square root of volume. There-

fore, large stores and vehicles are greatly favored by

logistic enterprises. Whereas production stores can

afford uniformly conditioned facilities of maximum

size, distribution storage is in need of compartmenta-

tion and separate conditioning to meet the require-

ments of different product groups. Towards the end

of logistic chains, at the retail outlets, storage facil-

ities and deliveries become necessarily smaller, dic-

tated by high surface charges and problems of

accessibility in cities. At the same time, compartmen-

tation and separate conditioning becomes more

problematic.

0154The same reason, low cost linked to a high degree

of protection, favors large appearances for transfer

operations. Warehouses exist which handle whole

transport units, i.e., containers, porthole or integral

reefers, but also flats with superstructures to be

covered by an insulated hood when in transit. Mostly,

tbl0008 Table 8 Average production and distribution costs for three main food chains (Netherlands, FI kg

1

)

Meat andmeat products Milkand dairy products Fruitand vegetables

Preserved Fresh

Primary product 5.0 0.75 1.43

Processing and packaging 0.92 0.27 2.71 0.39

Wholesale trade 0.62 0.06 0.54 0.17

Retail trade 3.10 0.27 1.31 0.55

Consumer price 9.64 1.35 5.99 2.54

From Meffert HFTh (1990a) Economic developments pertinent to chilling foods. In: Chilled Foods, the State of the Art. London: Elsevier Applied Science,

with permission.

Mainframe computer

Management

information system

Local reports

Production line

Bar-code printer

Barcode reader

Modem

Interface

Cold store

Distribution

center

Retail

stockroom

Modem

Hand-held

computer

Hand-held

computer

Modem

Host computer

fig0005 Figure 5 Schematic presentation of a system for a computer-

assisted guidance, management, and supervision system of a

cold-chain system. From Nowotny S (1988) Computer-modeling

of cold chain systems. In: Cold Chains in Economic Perspective.

Paris: International Institute of Refrigeration.

5848 TRANSPORT LOGISTICS OF FOOD

however, unit loads (on pool-pallets) are the normal

appearances for transshipment. Smaller units, carts

with supporting superstructures, are favored at the

retail level for closed-circuit operations.

0155 As the transportation link tries to maximize deliver-

ies, a trend emerges leading to maximum size, multi-

compartment, multitemperature, expensive vehicles.

This tendency towards large vehicles is counteracted

by traffic situations and regulations, which restrict

the accessibility of cities and, because of the need

for supplementary deliveries JIT, add to the logistic

costs.

0156 Also, the degree of protection is generally greater at

large facilities and operations, owing to their more

sophisticated technical equipment and better supervi-

sion of operations. For this reason, large-scale oper-

ations in logistic chains for conditioned products

serve two purposes – low cost and good protection

of quality. Costs per unit per time increase remark-

ably towards the end of the chain, where smaller

facilities are in use, together with decreasing protec-

tion. Longer lead-times for storage at large facilities

lead to cost and quality savings. Shorter lead-times at

small facilities are favored for the same reason, and

reduce inventory costs. An effective information

system is necessary to guarantee the continuity of

the product flow to the customer.

Location of Facilities along the Logistic Chain

0157 The general model of a logistic chain for agrofood

products is the tree of Pythagoras, showing the col-

lecting and the distributing function on both sides of

the trunk. Small facilities are located at the beginning

and at the end of the logistic system, implying high

flow speeds for cost and quality reasons. Large

facilities mark the middle of the trunk, the center

of the logistic system.

0158For production with a quality life longer than the

minimum lead-time through all the links of the chain,

a buffer station can most economically, in terms of

both cost and quality, be situated at the point of

maximal aggregation.

0159If quality life and lead-time are of the same magni-

tude, the buffer function tends to move towards the

end of the chain. The storage function of all the

preceding links is minimized for a maximization of

quality at the retail outlets. The retailers, however,

favor daily shopping, which generates greater sales,

and reduces quality problems that result from long

residence times at suboptimal conditions at the retail

end of the chain. The buffer function is thus located at

the wholesalers and distribution centers, which often

have to take care of the delivery service as well,

governed by effective order processing.

Combination of Product Flows

0160A powerful means of reducing logistic costs is given

by the combination of goods in consecutive links of

the distribution chain; Table 9 gives an example.

0161The possibilities for combination depend on the

required conditions and lead-times, but can also be

enlarged by multicompartment, multicondition facil-

ities for storage and transportation. In this field, pro-

tective packaging for specific products has its special

merits, allowing for combinations which are other-

wise impossible.

0162Considerable reductions of transportation costs are

reported through savings on labor, equipment, and

energy costs. The total savings percentages are much

less spectactular, but interesting enough with respect

to price competition. In storage links, the advantages

of combination are more indirectly realized by sim-

plified, uniform inventory administration and order

processing.

tbl0009 Table 9 Integration of product flows for delivery at retail level; developments in Europe (Netherlands) and USA, 1984–1990

Product group Conditioning Average volume flow (%)

Europe(NL) USA

1 2.1 2.2 2.3 2.4

General grocery n 52 D 53 D 42 D 42 D 67 D 76 D

Meat products ch 8 R 6 R 23 D

Cheese/eggs ch/n 2 R 2 R 2 R

Fruits and vegetables ch/n 18 R 11 R 17 R

Frozen food df/f 2 R 2 R 2 R 9 R 7 D

Fresh meat ch 5 R 5 R 7 R

Milk products ch 13 R 9 R 13 R 13 R 13 R 13 R

Bakery products n 10 R 7 R 11 R 11 R 11 R 11 R

100 100 100 100 100 100

First digit (1,2) represents different stores; second digit (1–4) represents steps of development.

n, nonconditioned; ch, chilled; f, frozen; df, deep-frozen; D, from distribution center; R, from regional depot/wholesaler.

TRANSPORT LOGISTICS OF FOOD 5849

Logistical Policy

0163 In agrofood logistic systems, storage and trans-

portation – the main activities in all logistic systems

– are, in addition, characterized by critical design

considerations originating from product quality de-

velopment in time, and conditioning. The two activ-

ities compete for minimum costs, by aiming for the

largest possible facilities in the relevant links of the

transport chain, but under the limiting influences of

differentiated product requirements and restrictions

imposed by high housing costs and traffic regulations

in cities.

0164 Total cost analysis provides a methodology for the

integrated design of activities along the whole chain

of operation. For a complete analysis in the planning

phase, a wide variation of design alternatives has to be

considered: alternative location of primary (produc-

tion), secondary (distribution), and tertiary (retail)

storage facilities, type of transportation, shipment

size, appearances, equipment for processing, condi-

tioning, and handling.

0165 As decision criteria, maximum service, maximum

profit, maximum competitive advantage or minimum

investment (hired services) may be used. Regardless

of the chosen strategy, the desired level of customer

service should be accomplished at minimum total

cost. The number of possible alternatives to reach

this aim can only be tested by the use of mathematical

models. The formulation of a total cost analysis is not

without practical problems, especially the appreci-

ation of quality degradation.

0166 Limitations of throughflow time deal only with the

general logistic aspect of product flow. The limitation

of conditions, the most important of which is tem-

perature, is considered the second most important

aspect for perishable products, whereas only the com-

bination of the two can yield the appropriate criteria

in terms of quality maintenance in the chain.

0167 Supervision of chain processes, therefore, should

be based on information on time–temperature load

on the product rather than only time-based informa-

tion (shortest remaining shelf-life instead of FIFO as

the management criterion). This requires a new

system of control, which in its simplest form is pre-

sented by cheap physicochemical, directly readable,

time–temperature integrators for each lot of product.

A more suitable approach can be expected from the

application of microelectronic sensors backed up by a

computer-assisted inventory management.

Standards and Recommendations0168

0169

ANSI, American National Standards Institute. MH

10.2–1973.

0170AUF, Australian United Fruit and Vegetable Organ-

ization. 1980, Product Manual.

0171EC, European Community. Directive Deep Frozen

Food for Human Consumption, 1990, Brussels.

0172ECE, Economic Commission for Europe. Agreement

on the international carriage of perishable foodstuffs

and on the special equipment to be used for such

carriage (ATP), Geneva, 1970, and amendments,

revised 1991.

0173Food Marketing Institute. MUM-project. Trade

Practice Recommendations for the Fresh Fruit and

Vegetable Industry, Washington, DC (1982).

0174IIR/IIF, International Institute of Referigeration,

Saving of energy in refrigeration, Paris, 1980. Re-

frigeration of perishable products for distant markets,

1982. Cold chains in economic perspective, 1988.

0175ISO, International Organization for Standardization.

3674-1984, Packaging – Unit Load Sizes – Dimen-

sions. 3394-1984, Dimensions of rigid rectangular

packages – Transport packages. 6780-1988, Gen-

eral-purpose pallets for through transit of goods –

Part 1: Principal dimensions and tolerances.

1496/2-1988, Series 1 freight containers – Specifica-

tions and testing – Part 2: Thermal containers.

0176SAA, Standards Association of Australia. AS 2348-

1980, Modular Unit Loads.

0177UK, Food Hygiene Regulations, 1990, London.

See also: Storage Stability: Mechanisms of Degradation;

Parameters Affecting Storage Stability; Shelf-life Testing

Further Reading

Broetz W (1958) Grundriss der Chemischen Reaktionstech-

nik. Bergheim/Weinstrasse: Verlag Chemie.

Derens E, Canourges EM, Bennahmias R and Billiard F

(1990) Les enregistreurs de temperature. Revue General

du Froid, July/August: 63–68.

Jordan JL, Shewfelt RL, Prussia SE and Hurst WC (1985)

Estimating the price of quality characteristics for toma-

toes. Horticultural Science 20(2): 203–205.

Karel M (1982) Prediction of shelflife of stored food. In:

Refrigeration of Perishable Products for Distant

Markets, pp. 202–209. Paris: IIF/IIR.

Kast FE and Rosenzweig JE (1985) Organisation and

Management. New York: McGraw-Hill.

Koelemeijer K (1991) A conceptual model of customer

service evaluation. In: Bradley F (ed.) Marketing

Thought around the World. Dublin: University College.

Labuza ThP (1982) Shelf Life Dating of Foods. Westport,

CT: Food and Nutrition Press.

LaLonde BJ, Cooper MC and Noordewier TG (1988) Cus-

tomer Service, a Management Perspective. Oak Brook:

Council of Logistic Management.

LaLonde BJ and Zinszer PH (1976) Customer Service:

Meaning and Measurement. Chicago, IL: National

Council of Physical Distribution Management.

5850 TRANSPORT LOGISTICS OF FOOD

Levenspiel O (1972) Chemical Reaction Engineering, 2nd

edn. New York: Wiley.

Meffert HFTh (1990a) Economic developments pertinent

to chilling foods. In: Chilled Foods, the State of the Art.

London: Elsevier Applied Science.

Meffert HFTh (1990b) Chilled foods in the market place.

In: Processing and Quality of Foods, vol. 3. London:

Elsevier Applied Science.

Meffert HFTh (1990c) Quality development of foodstuffs

under time–temperature conditions in cold chains. In:

Progress in the Science and Technology of Refrigeration

in Food Engineering. Paris: International Institute of

Refrigeration.

Nowotny S (1988) Computer-modelling of cold chain

systems. In: Cold Chains in Economic Perspective.

Paris: International Institute of Refrigeration.

Rich E (1988) Artificial Intelligence. New York: McGraw-

Hill.

Saguy I and Karel M (1980) Modelling quality determin-

ation during food processing and storage. Food Technol-

ogy 34(2): 78–85.

Schoorl D and Holt JE (1981) Fresh fruit and vegetables

distribution management of quality. Scientia Horticul-

turae 17: 1–8.

Shewfelt RL, Prussia SE, Hurst WL and Jordan JL (1985) A

system approach to the evaluation of changes in quality

during postharvest handling of southern peas. Journal of

Food Science 5: 169–772.

Simpson R, Lee Ken-Youn and Torres A (1989) A manage-

ment tool to improve microbial quality of refrigerated

foods. In: Technical Innovations in Freezing and Re-

frigeration of Fruits and Vegetables. Paris: International

Institute of Refrigeration.

Spiess WEL (1988) Changes in quality of deep frozen food

on the frozen food chain. In: Cold Chains in Economic

Perspective. Paris: International Institute of Refriger-

ation.

Westerterp KR, van Swaail WPM and Benneckers AACM

(1984) Chemical Reactor Design and Operation.

Chichester: John Wiley.

TRICARBOXYLIC ACID CYCLE

D A Bender, University College London, London, UK

Background

0001 The tricarboxylic acid cycle is the major energy-

yielding metabolic pathway in cells, providing the

greater part of the reduced coenzymes that will be

oxidized by the electron transport chain to yield

adenosine triphosphate (ATP). The pathway is some-

times known as the citric acid cycle, or the Krebs’

cycle, after its discoverer, Sir Hans Krebs. In addition

to its role in energy-yielding metabolism, and the oxi-

dation of 2-carbon units, the cycle is also the major

pathway for interconversion of 4- and 5-carbon com-

pounds in the cell, many of which arise from, or are

intermediates in the synthesis of, amino acids. Oxa-

loacetate, a key intermediate in the cycle, is the main

precursor for gluconeogenesis in the fasting state.

Reactions of the Tricarboxylic Acid Cycle

0002 As shown in Figure 1, the tricarboxylic acid cycle

provides a pathway for the oxidation to carbon

dioxide and water of the acetate moiety of acetyl coen-

zyme A (CoA) arising from the oxidative decarboxyla-

tion of pyruvate (the end product of glycolysis), the

b-oxidation of fatty acids, the metabolism of ethanol,

ketone bodies, and a number of amino acids. For each

mole of acetyl CoA oxidized in this pathway, there is a

yield of 12 ATP equivalents, arising from:

00033 nicotinamide adenine dinucleotide (NAD

) re-

duced to NADH, equivalent to 9 ATP when reox-

idized in the electron transport chain;

00041 flavoprotein reduced, leading to reduction of

ubiquinone, equivalent to 2 adenosine diphos-

phate (ADP) when reoxidized in the electron trans-

port chain;

00051 guanosine diphosphate (GDP) phosphorylated

to guanosine triphosphate (GTP), equivalent to

1 ATP.

The four-carbon intermediate, oxaloacetate, reacts

with acetyl CoA to form a six-carbon compound,

citric acid. The cycle is then a series of steps in

which two carbon atoms are lost as carbon dioxide,

followed by a series of oxidation and other reactions,

eventually reforming oxaloacetate. The CoA of acetyl

CoA is released, and is available for further formation

of acetyl CoA from pyruvate, fatty acids, or ketone

bodies.

0006Although oxaloacetate is the precursor for gluco-

neogenesis, fatty acids and other compounds that give

rise to acetyl CoA or acetoacetate cannot be used for

net synthesis of glucose. As can be seen from Figure 1,

TRICARBOXYLIC ACID CYCLE 5851

although two carbons are added to the cycle by acetyl

CoA, two carbons are lost as carbon dioxide in each

turn of the cycle. Therefore, when acetyl CoA is the

substrate, there is no increase in the pool of tricar-

boxylic acid cycle intermediates, and therefore oxa-

loacetate cannot be withdrawn for gluconeogenesis

when acetyl CoA is being metabolized.

0007Although citrate is a symmetrical molecule (carbons

1 and 2 are equivalent to carbons 5 and 6), it behaves

asymmetrically in the cycle. When tissue is incubated

with [

C]acetyl CoA in the presence of malonate, an

inhibitor of succinate dehydrogenase, there is no re-

lease of

, despite the fact that 2 mol of CO

are

released in the sequence of reactions between citrate

SCoA

Acetyl CoA

CoASH

COOH

CHOH

COOH

Aconitase

Cis-aconitate

Malate

dehydrogenase

Oxaloacetate

Citrate synthase

Citrate

Isocitrate

COOH

Ketoglutarate

(oxo-glutarate)

Malate

COOH

Fumarate

NADH

NAD

Fumarase

Isocitrate dehydrogenase

CoASH

NAD

NADH

Ketoglutarate dehydrogenase

FADH

FAD

Succinate dehydrogenase

Succinyl CoA

Succinyl CoA synthetase

CoASH

GTP

GDP, P

SCoA

Succinate

fig0001 Figure 1 Tricarboxylic acid cycle. Citrate synthase EC 4.1.3.7, aconitase EC 4.2.1.3, isocitrate dehydrogenase EC 1.1.1.41, ketoglu-

tarate dehydrogenase EC 1.2.4.2, succinyl CoA synthase EC 6.2.1.4, succinate dehydrogenase EC 1.3.5.1, fumarase EC 4.2.1.2, malate

dehydrogenase EC 1.1.1.37.

5852 TRICARBOXYLIC ACID CYCLE

synthetase and succinate dehydrogenase. The two

carbon atoms that are lost in the first turn of the

cycle are not the same two atoms added from acetyl

CoA. This is because citrate does not diffuse from the

active site of citrate synthetase into free solution, but

is channeled directly from the active site of citrate

synthetase to that of aconitase.

0008 The main regulation of the rate of tricarboxylic

acid cycle activity is by control of the activity of

isocitrate dehydrogenase, which is regulated by both

phosphorylation/dephosphorylation, and also by the

intramitochondrial ratio of NADH:NAD

, it is also

inhibited by NADH, and activated by ADP. When the

rate of entry of acetyl CoA into the cycle, and hence

the rate of formation of citrate, is greater than the rate

at which isocitrate undergoes dehydrogenation, aco-

nitase is inhibited by its product. The result of this is

that citrate can no longer be channeled from the

active site of citrate synthetase to aconitase, and

now leaves the active site of citrate synthetase into

free solution in the mitochondrial matrix. In most

tissues, free citrate can be transported out of the

mitochondria into the cytosol. Here, it can act both

to inhibit phosphofructokinase, so reducing the rate

of glycolysis and formation of acetyl CoA, and the

cytosolic as the source of acetyl CoA for fatty acid

synthesis (see below).

0009 a-Ketoglutarate dehydrogenase catalyzes a reac-

tion similar to that of pyruvate dehydrogenase – oxi-

dative decarboxylation and formation of an acyl CoA

derivative. Like pyruvate dehydrogenase, it is a thia-

min diphosphate-dependent enzyme. However, thia-

min deficiency does not have a significant effect on

the tricarboxylic acid cycle, because a-ketoglutarate

can undergo transamination to yield glutamate, which

is decarboxylated to g-aminobutyric acid (GABA).

In turn, GABA can undergo further metabolism to

yield succinate. This pathway, shown in Figure 2,is

sometimes called the GABA shunt; it provides an

alternative to a-ketoglutarate dehydrogenase in thia-

min deficiency, so that oxidation of acetyl CoA and

formation of ATP can continue.

0010 The reaction of succinyl CoA synthetase, the for-

mation of free succinate and CoA from succinyl CoA,

is linked to a substrate-level phosphorylation of GDP

to GTP, which is energetically equivalent to the for-

mation of ATP.

0011 In tissues that synthesize glucose in the fasting state

(liver, kidney, and intestinal mucosa), this reaction

also provides an important link between the rate of

tricarboxylic acid cycle activity and the withdrawal

of oxaloacetate for gluconeogenesis. The formation

of phospho-enolpyruvate from oxaloacetate, cata-

lyzed by phospho-enolpyruvate carboxykinase (see

Figure 4) requires GTP as the phosphate donor; the

major, if not only, intramitochondrial source of GTP

is the reaction of succinyl CoA synthetase. This means

that it is not possible to withdraw oxaloacetate from

the cycle for gluconeogenesis if this would result in a

slowing of the rate of cycle activity, and hence the rate

of formation of GTP.

0012Under conditions where ketone bodies are being

metabolized (especially in muscle and brain in the

fasting state), there is an alternative reaction that

bypasses succinyl CoA synthetase – direct transfer of

CoA from succinyl CoA on to acetoacetate to form

acetoacetyl CoA. This provides a link between the

rate of tricarboxylic acid cycle activity and the ability

to take up and utilize acetoacetate; if there is little

succinyl CoA available, little acetoacetate can be

utilized.

0013The sequence of reactions between succinate and

oxaloacetate is chemically the same as that involved

in the b-oxidation of fatty acids:

COOH

CoASH

COOH

Glutamate

decarboxylase

Glutamate

GAGA

(γ-aminobutyrate)

GABA

aminotransferase

Citric

acid cycle

Citric acid cycl

COOH

Ketoglutarate

COOH

SCoA

NAD

NADH

Succinic

semialdehyde

Succinic

semialdehyde

dehydrogenase

Ketoglutarate

dehydrogenase

Succinyl CoA

GTP

GDP + P

CoASH

Succinate

fig0002Figure 2 GABA shunt. Glutamate decarboxylase EC 4.1.1.15,

GABA aminotransferase EC 2.6.1.19, succinic semialdehyde

dehydrogenase EC 1.2.1.24, ketoglutarate dehydrogenase EC

1.2.4.2.

TRICARBOXYLIC ACID CYCLE 5853

.0014 Oxidation to yield a carbon–carbon double bond.

Although this reaction is shown in Figure 1 as being

linked to reduction of FAD, the coenzyme is tightly

enzyme bound, and succinate dehydrogenase reacts

directly with ubiquinone in the electron transport

chain.

0015 Addition of water across the carbon–carbon

double bond, to yield a hydroxyl group.

0016 Oxidation of the hydroxyl group, linked to reduc-

tion of NAD

, to yield an oxo-group, so reforming

oxaloacetate to undergo reaction with a further

molecule of acetyl CoA.

Citrate as the Source of Acetyl CoA for

Lipogenesis

0017The substrate for fatty acid synthesis is acetyl CoA.

However, the only source of acetyl CoA is intra-

mitochondrial, whereas fatty acid synthesis is a cyto-

solic process. Under conditions where fatty acids are

Glycolysis

in cytosol

COOH

O O

COOH

SCoA

Acetyl CoA

for fatty acid synthesis

CoASH

Citrate lyase

COOH

SCoA

Pyruvate

dehydrogenase

Acetyl CoA

Mitochondrion

CoASH

Oxaloacetate

Citrate synthase

Citrate

COOH

Citrate

ADP, Pi

ATP

Pyruvate carboxylase

Pyruvate

COOH

Pyruvate

Malic enzyme

NADPH

NADP

COOH

CHOH

COOH

Oxaloacetate

COOH

Malate

NADH

NAD

Malate dehydrogenase

fig0003 Figure 3 Citrate as the source of acetyl CoA for fatty acid synthesis. Pyruvate dehydrogenase EC 1.2.4.1, citrate synthase EC 4.1.3.7,

citrate lyase EC 4.1.3.6, malate dehydrogenase EC 1.1.1.37, malic enzyme EC 1.1.1.38, pyruvate carboxylase EC 6.4.1.1, phospho-

enolpyruvate carboxykinase EC 4.1.1.32.

5854 TRICARBOXYLIC ACID CYCLE

to be synthesized, and the rate of entry of acetyl

CoA into the cycle is greater than that required for

maintenance of ATP formation, free citrate is trans-

ported from the mitochondrial matrix into the cyto-

sol. Here, it undergoes cleavage to acetyl CoA and

oxaloacetate.

0018 Oxaloacetate cannot reenter the mitochondrion,

but undergoes the sequence of reactions shown in

Figure 3: reduction to malate, followed by oxidative

decarboxylation to pyruvate, which enters the mito-

chondrion, and is carboxylated to oxaloacetate. The

oxidative decarboxylation of malate to pyruvate,

catalyzed by the malic enzyme, is linked to the reduc-

tion of NADP

to NADPH. This reaction provides

half the NADPH required for fatty acid synthesis; the

remainder comes from the pentose phosphate path-

way of glucose metabolism.

Anaplerotic Reactions – Replenishing the

Supply of Tricarboxylic Acid Cycle

Intermediates

0019 If oxaloacetate is removed from the cycle for glucose

synthesis, it must be replaced, since if there is not

enough oxaloacetate available to form citrate, the

rate of acetyl CoA metabolism, and hence the rate

of formation of ATP, will slow down. Similarly, under

conditions of hyperammonemia, the reaction of glu-

tamate dehydrogenase leads to withdrawal of a con-

siderable amount of a-ketoglutarate, to the extent

that ATP formation is impaired, leading to coma

and convulsions.

0020 As shown in Figure 4, a variety of amino acids give

rise to tricarboxylic cycle intermediates, so permitting

removal of oxaloacetate for gluconeogenesis. In add-

ition, the reaction of pyruvate carboxylase is a major

source of oxaloacetate to maintain tricarboxylic acid

cycle activity.

0021 The metabolic fate of pyruvate, oxidative decar-

boxylation to yield acetyl CoA or carboxylation

to yield oxaloacetate, is determined by the relative

availability of acetyl CoA (which also arises from b-

oxidation of fatty acids and metabolism of ketone

bodies) and the need for oxaloacetate to maintain

tricarboxylic acid cycle activity. Pyruvate dehydro-

genase is inhibited by both NADH and acetyl CoA,

whereas pyruvate carboxylase has an absolute re-

quirement for acetyl CoA for activity. Thus, at times

when there is an abundance of acetyl CoA, pyruvate

will not undergo decarboxylation and oxidation in

the tricarboxylic acid cycle, but rather will be car-

boxylated to oxaloacetate. Once the pool of tricar-

boxylic acid cycle intermediates is adequate, further

oxaloacetate formed by carboxylation of pyruvate

can be used for gluconeogenesis.

Metabolism of Amino Acid Carbon

Skeletons – Gluconeogenesis From Amino

Acids

0022Acetyl CoA and acetoacetate arising from the carbon

skeletons of amino acids may be used for fatty acid

synthesis or can be oxidized as metabolic fuel, but

cannot be utilized for the synthesis of glucose (gluco-

neogenesis, see glucose metabolism). Amino acids

that yield acetyl CoA or acetoacetate are termed

ketogenic. Only two amino acids, leucine and lysine,

are solely ketogenic; isoleucine, phenylalanine, and

tryptophan yield both ketogenic and glucogenic frag-

ments. All the other amino acids yield carbon skel-

etons that can be used for gluconeogenesis.

0023The principal substrate for gluconeogenesis is oxa-

loacetate, which undergoes the reaction catalyzed

by phospho-enolpyruvate carboxykinase to yield

phospho-enolpyruvate, as shown in Figure 4. The

points of entry of amino acid carbon skeletons into

central metabolic pathways are shown in Figure 4.

Those that give rise to ketoglutarate, succinyl CoA,

fumarate, or oxaloacetate can be regarded as directly

increasing the tissue pool of tricarboxylic acid cycle

intermediates, and hence permitting the withdrawal

of oxaloacetate for gluconeogenesis.

0024Those amino acids that give rise to pyruvate also

increase the tissue pool of oxaloacetate, since pyru-

vate is carboxylated to oxaloacetate in the reaction

catalyzed by pyruvate carboxylase.

0025Gluconeogenesis is an important fate of amino acid

carbon skeletons in the fasting state, when the meta-

bolic imperative is to maintain a supply of glucose for

the central nervous system and red blood cells. How-

ever, in the fed state, the carbon skeletons of amino

acids in excess of requirements for protein synthesis

will be used mainly for formation of acetyl CoA for

fatty acid synthesis, and storage as adipose tissue

triacylglycerol.

Complete Oxidation of 4- and 5-carbon

Compounds

0026Although the tricarboxylic acid cycle is generally

regarded as a pathway for the oxidation of 4- and 5-

carbon compounds such as fumarate, oxaloacetate,

a-ketoglutarate and succinate arising from amino

acids, it does not, alone, permit complete oxidation

of these compounds. Four-carbon intermediates are

not overall consumed in the cycle, since oxaloacetate

is reformed. Addition of 4- and 5-carbon inter-

mediates may increase the rate of cycle activity (sub-

ject to control by the requirement for ATP), but

once the pool of intermediates is saturated, no more

can enter.

TRICARBOXYLIC ACID CYCLE 5855

0027 Complete oxidation of 4- and 5-carbon intermedi-

ates requires removal of oxaloacetate from the cycle,

and conversion to pyruvate, as shown in Figure 4.

This pyruvate may undergo decarboxylation to acetyl

CoA, which may be oxidized in the cycle, or can be

used for fatty acid synthesis or as a substrate for

gluconeogenesis.

See also: Amino Acids: Metabolism; Energy

Metabolism; Fatty Acids: Metabolism; Glucose:

Function and Metabolism; Ketone Bodies; Thiamin:

Physiology; Oxidative Phosphorylation