Proc. Nati. Acad. Sci. USA Vol. 77, No. 5, pp. 2439-2441, May 1980 Biochemistry

A suggestion for naming faces of ring compounds (stereochemistry/ring faces/receptor sites) IRWIN A. ROSE*, KENNETH R. HANSONt, KEITH D. WILKINSON*, AND MARY J. WIMMER*I *The Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; and tConnecticut Agricultural Experimental Station, New Haven, Connecticut 06504 Contributed by Irwin A. Rose, January 18, 1980

ABSTRACr Discussion of the topology of interaction of ring PROPOSED RULES compounds with macromolecules and receptors requires a system for naming the faces of the cyclic compound. An Rule 1 a/#-face nomenclature is suggested that is based on the clock- wise/counterclockwise direction of ascending numbering in If the compound contains only one ring or if a ring in a com- the ring with the lowest numbered unshared ring atom. This pound is not fused to another, the faces are designated as a if system is applicable to a very broad range of compounds: sugars, a clockwise progression around each ring leads from the lowest cyclic bases, steroids, cyclitols, porphyrins, etc., and molecules numbered ring atom to the next higher numbered atom of the with a single ring, fused rings, encompassing rings, and rings ring by the shortest route. If the progression is counterclockwise, formed by head-to-tail polymerization. the face designation is /3. The ring is examined as a plane regular Many compounds of biological interest owe their special polygon-i.e., conformation properties are ignored. When, as properties to the chemistry and the shape of cyclic components occurs rarely, alternate number symbols are used, the pair of of their structures. Particular orientations of nucleotides, numbered ring atoms used in application of the rule should coenzymes, hormones, and sugars with respect to receptor sites, follow these priorities: 1 and 2 precede la or 1'; and la and 2a enzymes, and other cyclic compounds may result from specific precede 1'. interactions at one or the other ring face. It is therefore im- portant to have a concise and generally applicable method for naming these faces. No such method exists. Furthermore, it seems that there has been no discussion of the characteristics that would be desirable in such a nomenclature. A partial solution to the above problem is available in the Re/Si system for naming the faces of trigonal atoms [refs. 1, 2 (p. 317)]. This can be applied to aromatic systems but it is un- suitable for extension to saturated rings. Because the assign- ments are sensitive to sequence-rule priorities, faces that to the chemist or biochemist seem obviously related may receive opposite names. A different model is provided by the steroid class of compounds. The terms front, B-face, and /3-face are widely used as alternate designations for the observed face of the steroid skeleton when it is drawn in the recommended way-e.g., structure I, 5-a-pregnane (3). The "/-face" in this usage is the face that lies behind the substituents officially said to be in the "/-orientation" (3). The other is the a-face (struc- ture I). In this paper we wish to propose a simple a//3 con- vention that can be applied to many classes of cyclic molecules and when applied to the steroids leads to the same designations already employed by steroid chemists. The proposal is based on the numbering of the atoms in molecules and therefore should give characteristic designations for all members of each family of compounds for which a convention of numbering exists (4, 5). This includes not only steroids but all purines and pyrimidines, pteridines and isoal- loxazines, all sugar rings, and many others in which a specific numbering scheme is recognized and is essential to scientific communication about a class of compounds. These numbering schemes are usually found in the primary literature, in text- books, and in reports on nomenclature. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "ad- vertisement" in accordance with 18 U. S. C. §1734 solely to indicate * Present address: Department of Biochemistry, School of Medicine, this fact. West Virginia University, Morgantown, WV 26506. 2439 Downloaded by guest on September 25, 2021 2440 Biochemistry: Rose et al. Proc. Natl. Acad. Sci. USA 77 (1980) Extensions of Rule 1. (i) The numbering of monomer units (ii) When the substrate for lysozyme fits into the active site that are combined in a "head-to-tail" fashion to give cyclic crevice, Asp-52 lies near the (-face and Gln-35 lies near the structures could be used to define the numbering direction of a-face of the N-acetyl-D-muramic acid pyranose ring, the a cyclic polymer unless an independent numbering system is glycosidic linkage of which is cleaved (7). specified. An example would be valinomycin, in which amino (iii) The finding that substitution at C-1, -3, or -5 did not acids and esters are the units. (ii) If a polygon can be drawn to alter the inhibitory effect of a-D-glucopyranose 6-phosphate encompass all of the unfused rings of a structure in an unam- for hexokinase (8) suggests that the (3-face of the pyranose ring biguous way, as in the case of the porphyrins (e.g., structure II), is free of important interactions with the enzyme. the common surface may be given the face designation of the (iv) The NAD+-malate dehydrogenase crystal structure (9) lowest numbered member ring. (Mii) If a pair of unfused rings shows the (-face of the nicotinamide ring directed toward an are joined by an exocyclic double bond, the common surface anion binding site, presumably the substrate binding site. This may be given the face designations of the lower numbered is consistent with the stereochemistry established for hydrogen ring. addition to the C-4 of the nicotinamide. (V) 02 binds to hemoglobin and myoglobin at the (-face of Rule 2 the heme (10, 11), the encompassing ring of which is shown by If the compound is made up of "ortho-fused" rings only, face heavy lines in structure II. designations of the entire system of rings are derived from the ring containing the lowest numbered unshared atom as speci- DISCUSSION fied in standard numbering for the compound. The system proposed offers the following advantages: A single NOTE: This rule ensures a correlation between the proposed procedure is available for aliphatic and aromatic rings and for face names and the a/(3 designations presently in use for steroid ortho-fused systems containing both types of ring. Because the ring substituents. For structure I the substituents above the system is based on ring numbering it should be endowed with plane of the paper are (3and by virtue of the counterclockwise the uniformity and durability built into such numbering in the ordering of the ring containing C-1 they project from the development of local systems of nomenclature. Face designa- (-face. If instead Rule 1 were applied to each ring, the faces tions should therefore be insensitive to substituent changes or of ring C would be given opposite names to those of rings A, B, minor structural changes. This allows one to easily generalize and D. Likewise, in the purines the smaller and larger rings in discussing the action of the enzyme on a series of structurally would have contrary face names. related compounds or on their binding to a receptor site-e.g., "the (-face is bound in all the related analogs that were Rule 3 tested." Ring structures that are modifications of molecules that are Our choice to identify a with clockwise seems natural and recognized by name or numbering as members of a particular leads to symbols compatible with the rules for steroids and class relate to the a/d3-face assignments of that class as fol- terpenes. On the other hand, a-D-glucopyranose has its ano- lows: meric -OH projecting from the (-face (in the L-series a-a- Rule 3.1. Rings that are added assume the a/13-face assign- nomeric substituents project from the a-face). Also, the so-called ments of the class if they are fused through adjacent atoms of 4A proton of NADH-i.e., the (pro-4R)-H of the pyridoxamide a ring of the basic class structure-i.e., are ortho-fused (e.g., the ring-projects from the face that would be named: in the six-membered phosphorus-containing ring in 3',5'-cyclic ade- present system. These lapses in mnemonic simplicity are un- nylic acid that is ortho-fused to the 3',4' atoms of the ribose fortunate and could be avoided by developing local systems for ring). face designation for each class of compounds. This suffers from Rule 3.2. Chemical changes in the lowest numbered ring, problems other than nonuniversality; the topology of a face will such as fission or change in ring size, do not alter the a/(3 sense usually have more to identify it than the orientation of one ring of the molecule as long as numbering of atoms and the name substituent. Ring atom numbering is more closely associated indicates that the molecule is a member of a standard class of with face topology. compounds. [In steroid nomenclature (3) the prefixes nor, The most frequent objection that has been raised to this homo, seco, and abeo (e.g., formula 98 in ref. 3) are used to proposal concerns the choice of the terms a and (l and the indicate the class relationship of such compounds, which pro- possibility of confusion with other usages of these symbols. Our vides the basis for the numbering system used.] choice of terms is provisional but clearly seems recommended Rule 3.3. If additional rings are appended to a basic class by their widespread acceptance in the steroid field for the same structure by fusion through nonadjacent atoms of a ring, the purpose. The practical usage of the terms would not seem to class-related rings of the molecule retain the class-related lead to ambiguity in the sense that a/(3 are modifiers of de- a/(3-face assignments. Reference should be made to the a/(3 scriptive nouns. Thus, a-face, a-anomer, a-carbon, etc., are faces of the primary ring system. (One cannot speak of the two different in the same sense that words beginning with the letter faces of the molecule because a single surface cannot be con- a are distinct. A second concern that might be expressed is that structed through its constituent rings.) To a limited extent faces numbering systems may change with time and that incom- of new rings formed by this type of bridging may be distin- patible systems may be used by different authors. These dif- guished as a and (3by the direction of numbered ring atoms as ficulties are not unique to sterochemistry and require that the given in Rule 1. numbering system that is used be specified. Such cases are Some Examples of Usage. (i) Watson-Crick base pairing rare. between purines and pyrimidines in the nucleic acids occurs We recognize that there are many cyclic natural products with a common orientation of their faces: a with a and (l with that cannot be represented by the single surface of an ortho- (3. Given an antiparallel arrangement of strands, the purines fused ring system. It may be appropriate in the future to de- will show their (-faces and the pyrimidines, their a-faces when velop additional face descriptors for classes of these compounds looking down the 5' strand (6). The pyrimidines and purines on an ad hoc basis. The a/(3-face system is capable of further of the 3' strand will therefore be seen from their (3- and a-as- development. Meanwhile, the examples presented above should pect, respectively, when viewed from the 3'-OH terminus. demonstrate the ease with which stereospecific interactions Downloaded by guest on September 25, 2021 Biochemistry: Rose et al. Proc. Natl. Acad. Sci. USA 77 (1980) 2441

among many molecules of biological importance can be de- 3. IUPAC-IUB Commission on Biochemical Nomenclature (1968) scribed with the proposed system. Biochim. Biophys. Acta 164,453-486. One may expect that some agreed-upon set of symbols for 4. Chemical Abstracts, Chemical Substance Index (1978) the alternate faces of ring compounds will stimulate studies of (Chemical Abstracts Service, Columbus, OH). topological aspects of molecular interactions as well as facilitate 5. Biochemical Nomenclature and Related Documents (1978) (The their description. Biochemical Society, London). H. M., Carrell, H. Note Added in Proof. Ligands and side chains of tetrapyrroles and 6. Neidle, S., Achari, A., Taylor, G. L., Berman, 269, corrinoids are given a/fl names based on whether they would appear L., Glusker, J. P. & Stallings, W. C. (1977) Nature (London) below/above the plane when these molecules are drawn in a standard 304-306. way (5, 12, 13). When viewed from above the plane the numberings 7. Imoto, T., Johnson, L. N., North, A. C. T., Phillips, D. C. & of the A rings of the standards are clockwise directed, contrary to the Rupley, J. A. (1972) Enzymes 7, 665-868. case for steroids and terpenes. Therefore, 02 of oxyhemoglobin is an 8. Rose, L. A., Warms, J. V. B. & Kosow, D. P. (1974) Arch. Biochem. from the f-face of the heme. a-ligand that projects Biophys. 164, 729-735. We thank Dr. Michael Liebman for drawing our attention to the face 9. Webb, L. E., Hill, E. J. & Banasak, L. J. (1973) Biochemistry 12, relationships of the nucleic acid base pairs and to Drs. Hans Hirsch- 5101-5109. mann, James Blackwood, Ernest Eliel, G. P. Moss, and Philip Pfeffer 10. Perutz, M. F., Rossmann, M. G., Cullis, A. F., Muirhead, H., Will, for helpful comments on early versions of these proposals. This work G. & North, A. C. T. (1960) Nature (London) 185,416-422. GM-20940 to was supported by U.S. Public Health Service Grants R. E., Strandberg, B. E., Hart, R. G., I.A.R., GM-06499 to M.J.W., GM-05432 to K.D.W., and CA-06927 and 11. Kendrew, J. C., Dickerson, RR-05539 to the Institute for Cancer Research; by National Science David, D. R., Phillips, D. C. & Shore, V. C. (1960) Nature Foundation Grant PCM 78-18501 to K.R.H.; and also by an appro- (London) 185, 422-427. priation from the Commonwealth of Pennsylvania to the Institute. 12. 1UPAC-IUB joint Commission on Biochemical Nomenclature (1979) Pure Appl. Chem. 51, 2251-2304. 1. Hanson, K. R. (1966) J. Am. Chem. Soc. 88,2731-2742. 13. IUPAC-1UB Commission on Biochemical Nomenclature (1974) 2. Hanson, K. R. (1976) Annu. Rev. Biochem. 45,307-330. Eur. J. Biochem. 45, 7-12. Downloaded by guest on September 25, 2021