A framework for teaching amino acid metabolism

72 do biochemists mean when ti~ey talk about energetic efficiency in these reims and ~, i~ practice, almost universal in current textbooks. )ustified? C;learlv a compa~i:.or, ~: z2~(~~ values for NADH oxidation and ATP synthesis i~ mi:,leading since the ceil iq l~ot ,,pvratl:~g under standard conditions. A spot check ~,f curr'nt text,, shows a surpri:,i~g ircq:tc>_v ,,t calculations carried out in these terms. AG is a measure of the maximum usefnl work (w) that a system may perform a~ld efficiency is thus definable as w/AG. Very relevant biological events in which ane may ask what is the value of this rado are transport of ions against a concentrathm gradient (akin ~,~ lifting a weight) and muscle contraction, both processes resulting from reactions il~volving net hydrolysis of ATP In relation to ATP sw~thesis we .~re defining work i,~ a >ome'~ ha! different sense, namely that of the effort of joining together ADP and P, but tl~e pEmcipl~ remains the same. Despite criticism, L2 it seems a legitimate exercise. If respiratory chain phosphorylation were 100 per cent efficient then w. the work done in ATP synthesis from ADP and Pl, would equal AG for the uncoupled oxidatiop, ,,f NADH. The efficiency of respiratory chail~ phosphorylation thus describes the extent of the conservation of the capacity to do useful work. If we could c o n s t r u , : : a fuel celi producing electrical energy from a membrane potentiai generated by an miequal distribution of ions, m turn sustained by ATP hydrolysis, the ATP being generated bv NADH oxidation, its over-all efficiency would be a real figure of practical significance. Reactions ii~ the living cell obey exactly comparable laws.

References

1Banks, B E (5 and Vernon, C A (1978) TIB."; 3, N150-8 2 Banks, B E C ai~d Vernon, C A (1979) TIBS 4, N53 3 Metzler, D E (1977) Biochemistry, pp 161 and 17B. Academic Press 4Mahler, H R and Cordes, E H (1971) BiologicalChemistry, 2nd edn, p 27. Harper & Row SLehninger, A L (1975) Biochemistry, 2nd edn, p 402. Worth 6Garratt, CJ (1979) TIBS 4, N52-3 7McGilvery, R W and Murray, T W (1974)JBiol Chem 249, 5845-50 8 Nishiki, K, Erecinska, M and Wilson, D F 11978) AmJ Physio1234, C73-81 9 Veech, R L, Lawson, ) W R, Cornell, N W, and Krebs, H A (1979)j Biol Chem 254, 6538-47 1° Morrison, J F and White, A (1967) EurJ Biochem 3,145-52 11 Morgan, H E and Parmeggiani, A (1964)J Biol Chem 239, 2440-5 t2 Williamson, J R (1965)J Biol Chem 2411, 2308-21 ~3Erecinska, M and Wilson. D F (1978) TIBS 3,219-23 14 Alexandre, A, Reynafarie, B and Lehninger, A L (1978) Proc Nat Acad Sci USA 75, 5296-300

A FRAMEWORK FOR TEACHING AMINO ACID METABOLISM LON J VAN WINKLE Department of Biochemistry Chicago College of Osteopathic Medicine 1122 East 53rd Street Chicago, Illinois, USA The metabolism of the twenty amino acids used in protein synthesis is one of the more difficult portions of a beginning course in biochemistry. An unfortunate consequence of this may be that many students memorize a myriad of apparently unrelated reaction sequences required 'for the exam', but do not attempt to integrate amino acid metabolism with other aspects of biochemistry. Without integration the student will be less likely to have an interest in or retain the 'learned' information. The preceding problem may result from the format used to present amino acid metabolism to students. An important general concept for teachers to remember is that students seem to learn better if one proceeds from a more general, over-all explanation of a topic towards more and more detailed explanations of smaller and smaller portions of the whole) Nevertheless, this concept is all too often forgotten especially when teaching amino acid metabolism. For example, the pathways by which amino acid carbon skeletons are metabolized, usually for ATP production or energy storage, are most often discussed one at a time or in small groups.2 3 4 The following approach for teaching amino acid metabolism has been devised to (a} facilitate conceptualization of amino acid metabolism as it is integrated with metabolism in general and (b) emphasize the metabolic similarities and differences among the amino acids.

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73 The amino acids are divided into two groups with respect to their utilization as energy sources in man (Fig 1). The 'non-fat like' group includes all non-essential amino acids (except tyrosine) plus the essential amino acid histidine. Metabolism of these glucogenic amino acids to intermediates of glycolysis or the Krebs cycle is not via reactions required for 20 amino acids degraded to intermediates in

glycolysis or the TCA cycle

Histidine and non-essential amino acids except tyrosine

II ]

Won-fatLike"

I

l,

Tyrosine and essential amino acids except histidine

"Fat-Like"

÷

,,

Topyruvate

F

To2 ketoglutarate

Cys Ala Ser Gly

Tooxaloacetate Asp Asn

Glu Gin Pro

To succinyl CoA

CoAand acetyl CoA

Met Thr Val

His

) ToAcetyl CoA plus fumarate only Phe Tyr

lie

Leu Lys

plus alanine

Arg

Trp

I. Figure 1

II

Glucogenic

Glucogenic and Ketogenic

Similarities in the degradation of amino acids

IL_2

Keto-

genic

fatty acid oxidation (Figs 1 and 2). In contrast, the second group of amino acids, which includes tyrosine and essential amino acids except histidine, are 'fat like' in their metabolism in that they are degraded via pathways containing some reactions required for fatty acid oxidation. Catabolism of the latter group usually results in the production of succinyl CoA through propionyl CoA (the pathway required for oxidation of fatty acids with an odd number of carbon atoms) and/or acetyl CoA (the usual product of fatty acid/3 oxidation) (Fig 3). Thus, except for those amino acids which result in succinyl CoA alone, the 'fat like' amino acids are obliged to be partly or wholly ketogenic (net glucose production is not possible). It is helpful to remind students that, although glucogenic amino acids can be used for net glucose production, glucose and glucogenic amino acids are also metabolized to fatty acids and 'ketone bodies'. Glucose

Ala~,,tll

Ser*-Gly

I Pyruvate I ' J ' /

CysI ~ "

7"f

Asn

(

/

~

, ~ ' K e t o n e bodies'

( ' a.yacids cycM

\ I 2-Ket°glutarate

Arg Figure 2 BIOCHEMICAL

EDUCATION

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Degradation of histidine and non-essentialamino acids except tyrosine 1980

I

Pro

74

Glucose

Trp

Crotonyl CoA

Pyruvate /N~

Leu

,~

~

Lys

/

~nebodie/s'

Oxaloacetate

f

A /

T,r

Figure 3

~,,,~[

I

l J" coAY 1

Succinvl

t_

_]

Degradation of tyrosineand essentialamino acidsexcept histidine The degradative pathways are generally simpler for non-essential than for essential amino acids and this may be related to the amino acid synthetic pathways retained by animals. It has been suggested that humans synthesize non-essential amino acids because these molecules have important metabolic roles other than as protein precursors, a Additionally, however, synthesis of non-essential amino acids is much simpler than synthesis of essential amino acids (Table 1). Only a single enzyme is required for synthesis of most non-essential NON-ESSENTIAL AMINO ACIDS Number of Eventual enzymes Amino Precursor(s) product required acid Ala Asp Asn Glu Gin Pr,, Arg Ser Gly Cys

Pyruvate Oxaloacetate Asp 2-ketoglutarate Glu Glu Glu 3-phosphoglycerate Set Ser & Met

Ala Asp Asn Glu Gill Pro Arg Set Gly Cys TOTAL MEAN

1 1 1 1 1 3 5 3 1 2 19 1.9

ESSENTIAL AMINO ACIDS Number ot Amino Eventual enzymes acid Precursor(s) product required Cys Thr Met lle Val Leu Lys

Tyr

or

Phe Trp His * 5-phosphoribosyl- 1-pyrophoxphat e

Table I

Sulfate & Ser Asp Homoserine & Cys Thr Pyruvate 2-ketoisovalerate Aspartate semialdelyde & pyruvate or Acetyl CoA & 2-ketoglutarate Erythrose 4phosphate & Phosphoenolpyruvate Chorismate & PRPI~ ATP & PRPP*

Cys 6 Thr 10 Homocysteine3 lie 5 Val 4 Leu 5 Lys 8

Tyr or Phe

10

Trp

6

His

9

TOTAL MEAN

6(, 66

The number of enzyme catalysed reactions requiredfor synthesis of non-essentialamino acids and the number of reactions that would be required if synthesis of essential amino acids had been retained in humans. (Compiledfrom references2 and 3.) amino acids from pre-existing substrates. In contrast, synthesis of essential amino acids would require an average of 6.6 additional enzymes per amino acid. Being heterotrophic, animals have no need for all synthetic pathways and elimination of the more complex pathways for amino acid synthesis could account for substantial energy savings. Since some

BIOCHEMICAL

EDUCATION

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1980

75 of the enzymes required in the latter pathways are quite complex, even more energy would be saved than is first apparent from counting the number of steps in the reaction sequences. Moreover, the rate of mutation probably fixes the amount of genetic information an organism can carry at some finite maximum. Elimination of the pathways for essential amino acid synthesis might (a) permit deletion of that portion of the genome with subsequent savings in replicative energy or (b) make that much more genetic 'space' available for evolution of other processes. However, although a heterotrophic way of life can eliminate the need for synthetic pathways, complex catabolic reaction sequences for essential amino acids have been retained since high levels of these compounds might be toxic and because excretion of these molecules would waste their energy content.

NON-ESSENTIAL AMINO ACIDS Number of Amino Eventual enzymes acid product required Ala Cys Ser Gly Asp Asn Glu Gin Pro

Pyruvate Pyruvate Pyruvate Set Oxaloacetate Asp 2-ketoglutarate Glu Glu

Arg

Glu TOTAL MEAN

Table 2

1 3 1 1 1 1 1 1 2 3 __ 15 1.5

ESSENTIAL AMINO ACIDS Number of Amino Eventual enzymes acid product required Val Thr Met Phe or Tyr lie Leu Lys Trp His

Propionyl CoA Propionyl CoA 2-ketobutyrate Acetoacetateand fumarate

9 2 3 6

Acetyl CoA and propionyl Coa 3-hydroxy-3-methyl glutaryl CoA Crotonyl CoA 2-ketoadipateand Ala Glu

6

TOTAL MEAN

5 7 8 4 50 5.5

The number of enzyme catalysed reactions requiredfor degradation of essential vs non-essential amino acids in humans. (Compiled from references z and 3.) The amino acids histidine, arginine, cysteine, and tyrosine require special consideration. Non-essential tyrosine has been included with the essential group because its carbon skeleton must be supplied in the diet usually as tyrosine or phenylalanine. Cysteine has been left with the non-essential group (Fig 1 and Table 2), even though its sulphur must be derived from dietary methionine in humans, because its carbon skeleton is not essential. Its synthesis as a non-essential amino acid in man requires only two steps and methionine and is easily retained. However, true de novo synthesis of cysteine from sulfate and serine requires six to seven enzymes as expected for essential amino acids (Table 1). Histidine and arginine, whose essential or non-essential natures have been most difficult to establish in humans, 3 fit most poorly into the classification scheme presented here. However, the number of enzymes that must be retained for arginine synthesis is deceptively large since three of the five synthetic steps are required for urea synthesis. Histidine is degraded to glutamate and thus fits into the 'non-fat like' group. On the other hand, its synthesis and degradation are relatively complex and thus it is best placed with essential amino acids when considering whether or not its synthesis is likely to be retained in animals. The extent to which various aspects of amino acid metabolism are discussed depends upon the nature of a particular course. More medicaUy-oriented courses can include a more complete discussion of vitamin cofactors, disorders of amino acid metabolism and enzymes of amino acid metabolism used in clinical diagnoses. The specifics of amino acid degradation and synthesis of non-essential amino acids can be included in medical biochemistry courses as time permits while a more comprehensive course might also include all synthetic pathways summarized in Table 1. In each course, however, the scheme presented above should provide a general metabolic framework (a) into which the student might fit details of amino acid metabolism and (b) with which he might connect other aspects of metabolism.

References

BIOCHEMICAL

EDUCATION

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1 Henderson,J F (1979)BiochemEd 7, 51 zWhite, A, Handler, P, Smith, E L, Hill, R L, and Lehman, I R (1978)Principlesof Biochemistry,6th edn, 648755. McGraw-HiU,New York 3McGilvery,R W (1979)Biochemistry:A FunctionalApproach,2nd edn, 545-615. W B Saunders,Philadelphia 4Orten,J M and Neuhaus,O W (1975)Human Biochemistry,9th edn, 293-355. Mosby,SaintLouis 1980