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ALTERATIONS IN BIOLOGICAL PATTERNS OF CELLS AS RELATED TO GENETIC ENZYME DEFECTS HERMAN M. KALCKAR* Until approximately 1928 it was generally believed that specific information carried in biopolymers involves proteins. Landsteiner gave us the concept ofhaptenes and specific determinant groups. Between 1925 and 1928 Oswald T. Avery, laterjoined by Michael Heidelberger and Walther Goebel, succeeded beyond any doubt in demonstrating that pure polysaccharides can carry specific immunological messages (antigens or haptenes ). The purified Type II pneumococcus substance did not possess any of the properties of a polypeptide and was even found to be free of nitrogen (see Addendum Í). In this year of 1928 a young Englishman, F. Griffith, discovered the pneumococcus transforming factor. Fifteen to sixteen years later Avery, MacLeod, and McCarty showed that the pneumococcus transforming factor is a polypeptide-free, polysaccharide-free biopolymer composed entirely of deoxyribonucleic acid (DNA). This triumphant discovery of DNA as a carrier of heritable messages may overshadow Avery's early discovery ofpolysaccharide antigens. Yet, as developments subsequent to 1928 will testify, the biological aspects ofthis discovery were as boundless as those deriving fromthe discovery oftransforming DNA preparations. About 1930 the discovery of the antigenicity of polysaccharides was translated into a more precise chemical language ofmono- and disaccharides through the joint work of Avery, Goebel, and Heidelberger. This field was further developed through the application ofhighly sophisticated end-group techniques developed by Heidelberger, Kabat, Morgan, Staub, Westphal, McCarty, and many others. In this article my aim is to try to * Biochemical Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. This article is reprinted, by kind permission, from On Cancer and Hormones— Essays in Experimental Biology (Chicago: University ofChicago Press, 1962). 47I integrate diverse sources offundamental knowledge concerning complex polysaccharides as related to metabolism and general cell biology. The scattered references will obviously stem from diverse fields. The pattern ofvarious sugars from which the complex polysaccharides are built up is ofkey importance to their biological action. As shown particularly clearly by Kabat, the specificity, especially ofblood-group mucopolysaccharides , is largely confined to the four or five terminal sugars. The vocabulary ofspecificity can be expressed invarious ways: (a) the composition ofsugars present; (b) the type oflinkages (a.or|3;i—>-4;i—>6; etc.); and (c) the presence or absence of branch points. This vocabulary is apparent in the human blood-group substances, in type-specific substances ofbacteria, and also presumably in the specificity ofvirus receptor spots. The enzymes which might affect the composition ofthe carbohydrate mosaics ofbiologically active mucopolysaccharides or lipopolysaccharides constitute a large variety. This part of the story starts with Leloir's discovery ofa type ofnucleotide hexoses composed ofa 5'-nucleotide linked through a pyrophosphate bridge to the phosphate ofa i-ester ofa hexose or hexosamine. One might call these nucleotide hexoses "active" hexoses or hexosamines. Let us start with uridine diphosphoglucose (UDPG), which we will designate UrPPG when used in chemical equations. Leloir discovered that in the living cell the galactose structure originates from the glucose structure by means ofthe reaction: UrPPG ^ UrPPGaI, catalyzed by a specific enzyme which is called Galacto-Waldense [1]. Since this name was also used for the over-all conversion of G-I-P to Gal-i-P, the name UDPGal-4-epimerase has been selected for the enzyme for the specific reaction between the two nucleotides [2]. Paralleling these observations was the demonstration by Leloir, Dutton, Storey, and others ofenzymes catalyzing the transfer ofglycosyl units from nucleotide hexoses to a variety ofmore or less specific glycosyl acceptors. Especially crucial was the demonstration by Leloir and co-workers that UDPG is a powerful glycosyl donor in polysaccharide synthesis of the living cell [3]. Cori ester, a-glucose-i-phosphate (or PG) is also a glycosyl donor, but in the living cell it serves in this capacity probably only in exceptional cases. How are these nucleotides synthesized in the cell? About ten years ago a Copenhagen team described a number of en472 Herman M. Kalckar · Cells and Genetic Enzyme Defects Perspectives in Biology and Medicine · Summer 1964 zymes that were "nucleotide transferases" ofone sort or another [2, 4] and that presumably play a role in the biosynthesis of the nucleotide hexoses. Many of them catalyze...


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