Polyamines in Mammalian Biology and Medicine (1979)

POLYAMINES IN MAMMALIAN BIOLOGY AND MEDICINE* H. GUY WILUAMS-ASHMAm AND ZOE N. CANEUAKISt Spermine, spermidine, and putrescine are three aliphatic amines of widespread biological occurrence whose molecular structures (fig. 1) were established over 50 years ago. Yet until past the middle of this century these polyamines were seldom allotted more than a line or two in the textbooks and were generally considered only as curios of physiological chemistry. In the interim, research on polyamines has blossomed into an astonishingly vigorous enterprise. H3N(CHj)4NH3 Putrescine H3N(CH2)4NH2(CH2)3NH3 Spermidine H3N(CH2)3NH2(CH2)4NH2(CH2)3NH3 Spermine Fig. 1.—The molecular structure ofthe three major polyamines in mammalian cells. All of the primary and secondary amine groups are shown in the protonated form, as occurs under physiological conditions. Some major results of recent investigations may be highlighted (Note 1). AU prokaryotes and eukaryotes manufacture putrescine and spermidine , whereas spermine production is largely confined to nucleated eukaryotic cells. A number of pathways for the biosynthesis and ?Studies from the authors' laboratories were supported by NIH research grants HD04592 and CA-16359. We are grateful to Ms. D. WaIz for excellent help in the preparation of the manuscript. This essay is dedicated to the memory of Chandrakant V. Dave. tBen May Laboratory for Cancer Research, Departments of Biochemistry and of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637. fVeterans Administration Hospital, West Haven, Connecticut 06516, and Departments of Pharmacology and Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.© 1979 by The University of Chicago. 0031-5982/79/2203-0072$01.00 Perspectives in Biology and Medicine · Spring 1979 \ 421 metabolism of polyamines have been uncovered in animals, plants, and microorganisms. Various polyamine biosynthetic enzymes are exquisitely regulated by innumerable agents that stimulate cell growth and differentiation, with resulting fluctuations in cellular polyamine concentrations . In cell-free systems, polyamines form tight, noncovalent complexes with many biomolecules, and especially with various nucleic acids, thereby influencing many reactions involved in the formation, turnover, and postsynthetic modification of DNA, RNA, and protein molecules. Spermine, spermidine, and putrescine also directly modulate, or participate in, other diverse metabolic processes and exert stabilizing effects on cell and organelle membranes. And clinical studies suggest that alterations in polyamines in some human body fluids may aid in the diagnosis or prognostic evaluation of certain diseases. Despite all this, many challenging questions in polyamine physiology remain unanswered. Here we shall dwell on several of these problems in the context of mammalian biology and medicine, with emphasis on neglected lines of research. I. Conformationally Flexible Polycations As its epithet implies, spermine was originally discovered in semen. Notwithstanding the large amounts of polyamines in the seminal plasma ofcertain species, these substances are preeminently ofintracellular significance in mammals. Polyamine levels in blood plasma and many other body fluids except semen are extremely low. Spermidine and spermine concentrations in most tissues lie within the range of 0.1-2 /¿mol per gram fresh weight; notable exceptions are the pancreas and the prostate gland in which higher values are encountered in some creatures. The spermidine/spermine ratio is frequently, but not invariably, highest in cells undergoing rapid growth or differentiation, and tends to drop in many tissues with advancing age or as a result of involution of many hormone-dependent organs precipitated by hormonal deprivation. Intracellular putrescine concentrations are strikingly lower than those of spermidine and spermine: values ofless than 0. 1 /nmol of putrescine per gram are usually observed in resting mammalian cells, and hardly ever exceed thrice this value in stimulated or malignant tissues. The levels and turnover rates of the three amines in higher animal cells can fluctuate enormously—often independently ofeach other and sometimes in a polyphasic fashion—in response to hormones, drugs, viral infections, and other factors. Assessment of polyamine functions in mammalian cells would obviously be facilitated by knowledge of their intracellular distributions. Unfortunately , technical difficulties have stood in the way of obtaining trustworthy data. Many attempts to study the associations of polyamines 422 I H. Guy Williams-Ashman andZoe N. Canellakis ¦ Polyamines in Biology andMedicine with subcellular fractions of homogenized tissues have been vitiated by uncontrollable redistribution artifacts. The only chemically reactive groups...