Download The Metabolism and Clinical Relevance of the Keto Acid Analogues

Clinical Science and Molecular Medicine (1978), 54, 589-593
EDITORIAL REVIEW
The metabolism and clinical relevance of the keto acid
analogues of essential amino acids
P. RICHARDS
St George's Hospital and Medical School, London SfVll ORE
Background
Essential amino acids are not themselves indispensible dietary requirements for the rat but their
carbon skeletons are (Rose, 1938). With two
exceptions, α-keto acid (Table 1) or α-hydroxy acid
analogues maintain the growth of rats almost as
well as the corresponding essential amino acids
(Richards, 1972). Lysine and threonine are the
exceptions: both are irreversibly deaminated
(Neuberger & Sänger, 1944; Elliott & Neuberger,
1950) and although the final test of feeding their
keto acid analogues has not been undertaken, the
cr-hydroxy acid analogue of lysine failed to main­
tain growth (McGinty, Lewis & Marvel, 1924).
Recently the clinical tail has wagged the bio­
chemical dog, provoking new interest in the extent
to which man can synthesize essential amino acids
from their analogues and in the possible thera­
peutic applications of essential amino acid
analogues.
Interest in the metabolism of essential amino
acid analogues in man originally arose from the
observations that about one-fifth of urea syn­
thesized is hydrolysed to ammonia in the gut
(Walser & Bodenlos, 1959) and that both healthy
and uraemic men can use ammonia nitrogen for
protein synthesis (Richards, Metcalfe-Gibson,
TABLE 1. a-Keto acid analogues of essential amino acids
including histldine
Amino acid
Valine
Leucine
Isoleucine
Phenylalanine
Methiohine
Tryptophan
Histidine
Lysine
Threonine
Keto acid
α-Ketoisovaleric acid
α-Ketoisocaproic acid
a-Keto-^-methylvaleric acid
/?-Phenylpyruvic acid
α-Keto-y-methiolbutyric acid
/i-Indolepyruvic acid
/8-Imadazolylpyruvic acid
α-Keto-e-aminocaproic acid
a-Keto-/?-hydroxybutyric acid
Ward, Wrong & Houghton, 1967). In addition it
was postulated that urea hydrolysis might sub­
stantially increase with the enlarged urea pool in
renal failure. It seemed probable that more am­
monia nitrogen would be used if it could be
channelled into the synthesis of both non-essential
and essential amino acids. In fact urea hydrolysis
hardly increases at all in renal failure (Walser,
1974; Varcoe, Halliday, Carson, Richards &
Tavill, 1975) and no more than about 5% of the
urea nitrogen released is re-used for albumin
synthesis, either during protein restriction (Varcoe
et ah, 1975) or when a low-protein diet is supple­
mented with the keto acid analogues of five
essential amino acids (Ell, Richards & Halliday,
1978). If a substantial quantity of urea nitrogen were
normally released as ammonia and reincorporated
into protein, urea would accumulate (or its
excretion would increase) when bacterial hydrolysis
of urea was suppressed by antibiotics. In fact,
neither the urea pool nor the urea excretion of
patients with chronic renal failure increased under
these circumstances (Mitch, Lietman & Walser,
1977). Currently, therefore, the interest in these
compounds has shifted from a theoretical role in
increasing nitrogen reutilization to their unex­
plained ability to reduce urea synthesis.
Synthesis of essential amino acids in man
Maintenance of nitrogen balance when the
appropriate analogues were added to a diet lacking
one or more essential amino acids has provided cir­
cumstantial evidence of transamination in man of
the cp-keto acid analogues of phenylalanine, valine,
leucine, isoleucine, tryptophan, methionine and
histidine in health and uraemia (Gallina,
Dominguez, Hoschoian & Barrio, 1971; Richards,
Brown, Houghton & Thompson, 1971; Rudman,
1971; Richards, Brown & Lowe, 1972; Walser,
Coulter, Dighe & Crantz, 1973). Hydroxy acids of
589
P. Richards
590
transaminase in human muscle has not yet been
measured but if similar to the rat the enzyme
balance in man would favour transamination of
branched-chain keto acids in preference to oxi­
dation, especially if they were given by intravenous
infusion.
The relative efficiences of enzymes affecting the
metabolism of essential amino acid analogues are
subject to several influences. Both alanine trans­
aminase and branched-chain amino acid trans­
aminase activity in rats vary with diet and renal
function. Interpretation of the effects of diet is
complicated by the fact that total starvation, a
protein-free diet, and a low-protein diet each exert
different effects. Feeding keto acid analogues of
branched-chain amino acids creates conditions
favouring their transamination because the specific
activity of branched-chain amino acid trans­
aminase increases, probably by direct induction of
the enzyme (Chan & Walser, 1978).
The efficiency with which keto acids replace
essential amino acids also depends upon other
factors such as the diet and the route of adminis­
tration of keto acids. The amount of tyrosine in the
diet, for example, determines the efficiency with
which phenylpyruvate replaces phenylalanine, and
the energy intake partly determines the result of
both growth and nitrogen-balance experiments.
The relative rates and completeness of absorption
of analogues and possible competition between
them may also influence their efficiency. The keto
analogues of valine and leucine were absorbed from
dog small intestine at only 60% of the rate of the
amino acids (Weber, Maddrey & Walser, 1977),
which are actively absorbed. Phenylpyruvate is
absorbed passively along a concentration gradient
in everted sacs of hamster small intestine and it
seems probable that the amino group is necessary
for recognition by the carrier involved in active
absorption (Lin, Hagihara & Wilson, 1962).
Urinary wastage does not appear to be a source of
inefficiency: less than 1% of the injected radio­
activity of 14C-labelled cr-ketoisovalerate was ex­
creted in the urine of rats (Chawla & Rudman,
1974).
methionine (Mitch & Walser, 1977a) and phenylalanine (Mitch & Walser, 1977b) have also more
or less maintained nitrogen balance. Further
indirect evidence has been derived from the
incorporation of ammonia 15N into phenylalanine
and valine during administration of their keto acids
(Giordano, Phillips, De Pascale, De Santo, Fürst,
Brown, Houghton & Richards, 1972), and from the
increase in plasma essential amino acid concentra­
tions after feeding their analogues (Rudman, 1971;
Sapir, Owen, Pozefsky & Walser, 1974). Finally,
transamination of an essential amino acid analogue
has been directly proved by the appearance of
t13C]valine in response to an intravenous infusion
of 13C-labelled cr-ketoisovalerate (Richards, Ell &
Halliday, 1977).
Efficiency of transamination of essential amino acid
analogues
The efficiency of conversion of cr-keto acid
analogues into essential amino acids depends upon
the competitive balance between reversible trans­
amination and oxidative decarboxylation (Fig. 1).
The outcome depends partly upon substrate con­
centrations and partly upon relative enzyme ac­
tivities. The reversible transamination and
deamination (reactions 1 and 2, Fig. 1) proceed
without preference to one product over the other,
the outcome depending upon the relative concen­
trations of these substrates.
Muscle has the highest capacity (although not
the highest activity per unit of tissue) for trans­
amination of branched-chain amino acids in the
rat, and liver has the greatest capacity for oxidation
of cr-keto acids (Harper, 1978). Species differences
are considerable: the relative branched-chain
amino acid dehydrogenase capacity values of liver,
kidney and skeletal muscle were 70, 12 and 10% in
the rat, 50, 13 and 20% in the monkey, and 30, 2
and 60% in skeletal muscle in man; the relative
increase in human muscle was an expression of the
greatly reduced specific activities of the enzyme in
liver and kidney, the absolute activity in muscle
being similar to the rat (Khatra, Chawla, Sewell &
Rudman, 1977). The branched-chain amino acid
CH3
H
I
\ CH=C-CO,H
CH,
Valine
NH,
CH,
CH,
CH=C-CO z H
CH3
0
o-Ketoisovaleric acid
\ CH-CO.H + CO,
CH,
Isobutyric acid
FIG. 1. Metabolic inter-relationships between ct-ketoisovaleric acid, valine and isobutyric acid. Reactions 1 and 2 are
catalysed by branched-chain amino acid transaminases and 3 by branched-chain amino acid
dehydrogenase/decarboxylase.
Keto acid analogues of essential amino acids
Gut bacteria might either decrease the effective
dose of keto acids by catabolizing them or enhance
their efficiency by transaminating and releasing
them for absorption as amino acids. Bacterial
activity in fact seems relatively unimportant in the
metabolism of amino acid analogues in the rat: less
than 10% of radioactivity given as 14C-labelled aketoisovalerate was recovered in the faeces with or
without antibiotic treatment (Chawla & Rudman,
1974); neomycin did not significantly alter the
efficiency of the keto analogues of phenylalanine,
leucine and valine (Chow & Walser, 1974) but a
more effective cocktail of neomycin, polymyxin
and bacitracin reduced the efficiency of a-ketoisovalerate in comparison with valine by 25-50%,
depending on the concentration of amino acid or
analogue in the feed, figures which took into
account the fact that antibiotic treatment itself
reduced the growth-stunting effect of a valinedeficient diet (Chawla & Rudman, 1974). The
unlikely possibility remains that the antibiotic
'cocktail' reduced absorption of a^ketoisovalerate,
but not of valine.
Both rat and human tissues have the capacity to
transaminate keto analogues of essential amino
acids. Perfusion of both rat liver and muscle with
keto analogues of valine, leucine, isoleucine, methionine and phenylalanine individually or together
produced essential amino acids, more when keto
acids were given individually than when given
together, probably because of competition for
transamination (Walser, Lund, Ruderman & Coul­
ter, 1973). Output of essential amino acids was not
the result of their intracellular displacement by
analogues, because the tissue-to-medium concen­
tration of essential amino acids was unchanged.
Glutamine was the major nitrogen donor in liver;
the principal nitrogen donor in muscle was not
identified (Walser et al., 1973). Leucine was also
synthesized from its keto analogue in human fore­
arm muscle: 52% of infused tr-ketoisocaproate was
extracted in a single passage and about one-third of
the extracted analogue appeared as leucine in deep
venous blood (Pozefsky & Walser, 1977).
Comparison of the efficiency with which an
analogue replaces its amino acid requires careful
definition of the term efficiency. Percentage
efficiency is best defined (Gaby & Chawler, 1976)
as:
mol of essential amino acid for a specified
physiological response
mol of analogue for the same physiological
response
Comparisons of efficiency must be made at
591
several different doses and the essential amino acid
under study must be a rate-limiting factor. Gaby &
Chawler (1976) correctly observed that if a less
than 30% reduction of essential amino acid intake
does not reduce growth rate an analogue which
was 70% efficient would still maintain growth and
appear to be 100% efficient. The alternative
definition of efficiency in terms of feed efficiency,
defined as weight gain/food intake, may under­
estimate efficiency of substitution: if, for example,
absence of an amino acid causes weight loss the
starting point is not zero efficiency but a negative
figure; thus if an analogue maintains weight but
supports no growth its efficiency would be zero by
definition in spite of the fact that it had some effect.
Efficiency of substitution may vary sub­
stantially at different intakes: for example, from
80% when the relative effects of one-quarter of the
daily requirement of valine for optimal growth was
compared with the molar equivalent of cr-ketoisovalerate to 37% when the diet contained twice the
requirement of valine or its analogue (Chawla &
Rudman, 1974). Others, such as ^ketoisocaproate, show little variation, its efficiency of
replacement being between 20 and 27% over a
wide range of intakes (Chawla, Stackhouse &
Wadsworth, 1975); the efficiency of phenylpyruvic
acid in place of phenylalanine was 50-70% at
different intakes (Chawla et al., 1975). Efficiency
of replacement of valine was greater when dietary
nitrogen was restricted (Chow & Walser, 1975a).
Clinical relevance
In chronic renal failure essential amino acid
analogues offer a means of delivering essential
amino acids without their nitrogen, thereby reduc­
ing nitrogen retention (by re-utilizing retained nonprotein nitrogen for essential amino acid synthesis)
without compromising nutrition (Schloerb, 1966;
Richards et al., 1967). Similarly, nitrogenous
intoxication might be minimized in patients with
liver failure, and in children with deficiencies of
urea-cycle enzymes (Close, 1974; Walser, 1975a).
Although potential benefit would be expected to be
limited to the effects of withdrawing nitrogen from
the non-protein nitrogen pool to convert the
analogues into an optimal supply of essential amino
acids (without reasonable expectation of further
benefit from the generation of an excessive supply
of amino acids), the therapeutic effects of essential
amino acid analogues are apparently greater than
this (Richards, 1975).
A substantial improvement in nitrogen balance
and reduction in blood urea concentration was
592
P. Richards
obtained when analogues were added to an already
marginally sufficient diet (Walser et al., 1973). The
improvement could not be attributed solely to reutilization of retained nitrogen because the change
in nitrogen balance was greater than if the
analogues had been transaminated with complete
efficiency and was greater than the benefit obtained
from essential amino acids themselves (Walser,
1975b). Further, the reduction of urinary urea
nitrogen induced by daily infusions offiveketo acid
analogues with the remaining four essential amino
acids continued for several days afterwards (Sapir
et al., 1974). Likewise infusions of only the
branched-chain analogues during the first week of a
total fast reduced urinary urea nitrogen excretion
during that week and the next (Sapir & Walser,
1977). Possibly a disproportionately great effect of
branched-chain amino acids, especially leucine,
upon the regulation of protein synthesis (Kirsch,
Frith & Saunders, 1976; Harper, 1978) may
explain the wider anabolic effects of a branchedchain keto acid supplement. Whatever the mechan­
ism, several lines of evidence converge upon the
conclusion that essential amino acid analogues
have an anabolic action which is not simply
explained by their transamination to essential
amino acids or to their acting as a 'nitrogen sponge'
(Gaby & Chawla, 1976).
It is difficult to prove that any supplements
(essential amino acid or keto acid) confer a longterm nutritional benefit, both because of the
difficulty in setting up appropriate nitrogen-balance
studies and because of the paucity of other
measures of nutrition. Essential amino acid supple­
ments to a 16—20 g of protein daily diet improved
the nitrogen balance of uraemic patients
(Bergström, Fürst & Noree, 1975) and there are
substantial theoretical and now some experimental
grounds for believing that anything essential amino
acid analogues can do in uraemia their analogues
might do better. Clinical benefit has also been
described (Walser et al., 1973; Walser, 1975b;
Noree & Bergström, 1975), but is difficult to
measure.
The usefulness of essential amino acid analogues
in the treatment of liver failure has yet to be defined
but may be enhanced by the reduced activity of
branched-chain keto acid dehydrogenase in
cirrhotic liver (Khatra et al., 1977). Infusion of five
essential amino acid analogues and four essential
amino acids to cirrhotic patients with portosystemic encephalopathy lowered blood ammonia
concentration but clinical benefit was hard to judge
(Maddrey, Weber, Coulter, Chura, Chapanis &
Walser, 1976). Isolated results of treatment of
children with urea-cycle enzyme deficiencies have
been impressive and encouraging. Plasma am­
monia, glutamine and alanine were reduced in a 13
year-old girl with carbamyl phosphate synthetase
deficiency whose health greatly improved
(Batshaw, Brusilow & Walser, 1975, 1976).
Plasma ammonia was reduced to normal and
citrulline by 50% in an infant with neonatal
citrullinaemia; it became possible to improve the
diet with improved growth and development and
diminished symptoms (Thoene, Batshaw, Spector,
Kulovich, Brusilow, Walser & Nyhan, 1977).
Treatment with essential amino acid analogues is
feasible. Although the keto acids are unstable their
sodium and especially their calcium salts are much
more stable; unpublished work suggests that their
stability is sufficient for clinical use, especially if
kept dry. The hydroxy acid analogues are at least
as stable and are easier to prepare than the keto
acids; current evidence suggests that they are
effective by first being oxidized to the keto acid
(Gordon, 1965). The finding of both branchedchain keto acids and hydroxy acids in the urine of
patients with maple-syrup urine disease (Scriver &
Rosenberg, 1973) indicates that the enzymatic
capacity for the conversion of hydroxy to keto
acid almost certainly exists in man. On balance
essential amino acid analogues are neither more
nor less pleasant to take than the amino acids
themselves; both may sometimes induce nausea
and vomiting. Hypercalcaemia sufficient to cause
symptoms develops in a small proportion of
patients given substantial amounts of calcium with
the analogues (Mitch, Gelman & Walser, 1978),
but no other serious unwanted effects have been
described.
Key words: amino acids, keto acid analogues,
transamination.
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