biochemists alcohol problem: a case of addiction to the wrong concepts?

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  • 3t0 T I B S - Sep tember 1983

    forensic, not metabolic sense) is its use to detect adulterants. For instance, adultera- tion of honey, which is usually formed from C-3 photosynthetic plants, can be detected by measuring IaC:I~C ratios; the slight dis- crimination of ribulose bisphosphate carboxylase-oxygenase for x2C allows for detection of sucrose and fructose-glucose from cane or corn, which are C-4 plants. DNA hybridization - especially in view of increased speed and accuracy afforded by the recA gene product and other advances in techniques a~.17 - might be used to detect the adulteration of a food with tissue from an inferior source. In the even more distant future, isolated chemoreceptor proteins may serve as potent analogs for the sensory evaluation of foodstuffs.

    Hydrophobic interactions Protein-protein interaction has been

    invoked to predict the behavior of dehy- drated foods, the rheology of flour doughs and the texture of meat. Limited proteolysis frequently results in special peptide-pep- tide interactions which, usually in combina- tion with disulfide bonds, can account for the so-called functional properties of many foods - baked goods via gluten alteration, dairy products via u-casein structure and

    milk clotting and food protein ingredients such as egg albumin, soy protein, gelatin and casein. These acquire such desirable functional properties as foamability, foam stability, whippability, viscosity, 'mouth feel' and moisture retentativeness.

    Hydropbobicities of certain di- and oligopeptides apparently determine whether they taste bitter and also whether they can be incorporated into 'plastein' ostensibly formed by reverse action of freshly added proteinases to proteolysates. Hydrophobic interaction in recovery of enzyme activity and protein tertiary structure via refolding TM may be relevant in the food industry's struggle to rationalize processes and optim- ize products.

    References documenting most of the statements in this review can be found in the author's recent book TM. With few excep- tions only references not cited therein are listed below.

    References 1 Love, R. M. (1980) Trends Biochem. Sci. 5, 3-6 2 Buscber, R. W. and Hobson, G. E. (1982)J.

    Food Biochem. 6, 147-160 3 Malmstrom, B. G. (1982)Annu. Rev. Biochem.

    51, 21-59 4 Litchfield, J. H. (1983) Science 219,740-746 5 Hershko, A. and Ciechanover, A. (1982) Annu.

    Rev. Biochem. 51,353-364 6 Parkin, K. L. and Hultin, H. O. (1982) FEBS

    Lett. 139, 61~a4 7 Komer, A. and Pawelek, J. (1982)Science, 217,

    1163-1165 8 Jolles, P. and Henschen, A. (1982) Trends

    Biochem. Sci. 7,325-328 9 Payen, F. W. and Persoz, J. F. (1833) Ann.

    Chim. Phys. 53, 73-92 10 Roberts, J. C. (1980) Trends Biochem. Sci. 5,

    VI-VII 11 Katchalski-Katzir, E. and Freeman, N. (1982)

    Trends Biochem. Sci. 7,427-431 12 Klibanov, A. M. (1983)Science 219, 722-727 13 Dambmann, C. and Aunstrup, K. (1981) in Pro-

    teinases and their lnhibitors. Structure, Func- tion and Applied Aspects (Turk, V. and Vitale, Lj., eds), pp. 233-244, Pergamon Press

    14 Kay, J. (1982)Biochem. Soc. Trans. (1982) 10, 277-291

    15 Shamasuzzaman and Haard, N. F. ( 1983)J. Food Sci. 48, 179-182

    16 Szabo, P. and Ward, C. (1982) Trends Biochem. Sci. 7,425--427

    17 Dressier, D. and Potter, H. (1982)Annu. Rev. Biochern. 51,727-761

    18 Kim, P. S. and Baldwin, R. L. (1982)Annu. Rev. Biochem. 51,459-489

    19 Schwimmer, S. (1981) Source Book o f Food Enzymology, Avi Publishing Co.

    ' 20 Rutloff, H., Huber, T., Zickler, F. and Mangold, K.-H. (1978) Industrielle Enzyme. lndustrielle Herstellung und Verwendung yon Enzyme- preparaten, VEB Fachbuchverlag

    Letters to the Editor Biochemists ' alcohol problem: a case o f addiction

    to the wrong concepts?

    SIR: In his concise and informative review on the problems of ethanol metabolism, Dr Dawson ( T I B S , 1983, Vol. 8, 195-197) exposed opposing hypotheses of 'what governs the rate of metabolic flux through the pathway'. He presented the conflicting evidence from a variety of authors and approaches which attempted to answer the question 'whether enzyme activity or NAD supply was the principal rate- determining factor'.

    By coincidence a few pages later Dr Porteous ( T I B S 1983, Vol. 8,200-202) discussed a fundamentally different approach to such problems, in the development of which I have played some part. May I therefore be permitted to make a few general remarks although I must stress that my experience in the field of ethanol metabolism is minimal.

    It would be absurd to suggest that either alcohol dehydrogenase activity or NAD 'supply' played no part in the metabolic flux and the various authors do not say this. What they do, however, appear to believe is that one of these factors must be 'the most influential'.

    It is at this point that I must give my

    opinion that the questions which axe being asked and the concepts which they reveal are based on a profound misapprehension of the kinetic nature and organization of metabolic systems. Let me pursue the 'walk-through-the-system' which Dr Dawson began in his diagram. The NAD 'supply' to the cytosol is clearly dependent on metabolic events within the mitochond- rion, hydrogen shuttles, ADP/ATP- ratios (which in turn depend on other well-known ATP generating pathways). Acetal- dehyde, which may act as an effector as well as a product is further transformed to acetate (dependent on NAD, ATP, etc.). All the associated enzymes and transport systems, apart from interacting with a variety of effectors, are subject to genetic control. The signals, which affect their synthesis and hence 'control' their concen- tration, are themselves generated within the system. Acetate enters further path- ways going to acetyl CoA etc. etc. (Please consult a reliable textbook or wall chart for the continuation of your 'walk'. At the end the diligent reader will find himself having traversed the whole of the biochemical world.) It is therefore clear that any

    particular flux (or other variable) is coupled, in some way, to every element in the system and hence, in principle, is affected by all of them. The question which 'factors' 'govern' or 'control' the flux must therefore be answered by: All factors. A systemic property, such as flux, is just that - the whole system is involved in determining its magnitude. Left at that, this would be a depressingly empty conclusion.

    We can, however, start from this and ask further questions: Are all factors equally involved? If not, is factor A more 'important' than factor B? What is the definition of 'importance' and what criteria should we apply? In attempting to answer such questions a quantitative theory of control has been developed. This is not the place to expound this in any detail (which can be found in the publications cited in Dr Porteous' letter). The central concept derives from the measurement of the response of a chosen variable to a small (in principle, infinites- simal) change in a chosen factor. This is expressed as a dimensionless number, a coefficient, whose magnitude represents precisely the effectiveness of share of the control of the factor or factors investi- gated. There is no place in the theory for

    1983. Elsevier Science Publishers BV. Amsterdam 0376 - 5(F07/83/$01.00

  • TIBS - September 1 983

    such a priori notions as 'rate-determining factor' 'sufficient supply' or 'excess enzyme' nor does it tolerate the confusion of treating enzyme concentrations and effector concentrations as equivalent. The systems analysis enables us to devise experiments (different from the traditional ones) which yield the quantitative para- meters of 'control'. The experimental evidence available indicates that the major share of the control is usually distributed among many enzymes and translocators.

    The insight gained from such an analysis then convinces us that the question: 'Is it the enzyme level or the NAD level which governs ethanol metabolism?' is unanswerable. What is

    answerable is a series of questions concerned with the distribution of control and with the quantitative evaluation of the various interactions using a methodology demanded by the theory. If this is done we shall end up with a precise array of numbers, the control coefficients, describ- ing the absolute and relative role which each element plays.

    The biochemists' alcohol problem which Dr Dawson diagnosed is a reflection of a more general malaise. The lack of progress in certain areas of biochemistry (and genetics) has, in my opinion, been due to the addiction of its practitioners to false concepts and, like all addicts, they are not very effective workers. The

    311

    pushers in this trade are, of course, the writers-of-books and the givers-of- lectures. They corrupt the young who are then hooked. All is not bleak, however. There/s a cure. In the last few years a number of strong minded people have undergone the cold turkey treatment. This consists of reading the relevant papers until one has understood them. Once free of the addiction, unlike an ex-alcoholic, one is cured for life.

    Department of Genetics, University of Edinburgh, West Mains Road, Edinburgh EH9 3JN, UK.

    H. KACSER

    SIR: 1 would like to congratulate A. G. Dawson on his article concerning the con- trol of ethanol metabolism (TIBS, 1983, Vol. 8, 195-197), which presents a very clear picture of the current controversy. There are, however, two points that I feel should be raised.

    The first concerns the assumption in the article that the activity of alcohol dehy- drogenase is affected by 'the adequacy of the NAD + supply'. Although it is commonly assumed that the decrease in ratio ofNAD + to ,NADH in liver during ethanol metabol- ism must reflect a significant