DONALD C.MORTIMER AND MARVIN J. JOHNSON
4098
seem to suggest polymerization rather than a shift of tautomeric forms. Ready polymerization of K-methylmyosinine was encountered in the work previously cited. l 3 This phenomenon was not s k’ ; I S rejmrted wcre studied further. ’The ~ J u e of r‘jlculated fro111 the major prdk of these curves. T * , L ~ L P ~much gre,ttcr tluii 1U or less tfiaii 0.i ~“tiitiot be tlctcrinuied ctccumtely with an eight-tube ti‘ttisfer. l’or this reason, ihe values of ihr ob1 irirtitioii cuefticieiits a5 reportcd in ‘1,iblc I
[ i l l I\-TRIBLTIOY
F R O X C ‘I’IIE
VOl. 74
for 4-methylamino-1-(3-pyridyl)- 1-butanol, nornicotine, anabasine and metanicotine deviate from a straight line function sufficiently to make i t impossible to calculate good values for the true partition coefficient or hydrolysis constant of these compounds. The observed values are in the correct order o f magnitude and are reported here for use in separations of these compounds by countercurrent t echniclues. ~JIIILAI’lEI,PIiIA
I&, P E N S A
I.)EPAK.IXEYT OF ~ I O C H E M I S T R Y ,CIJLLEGE OF AGRICULTURE, UNIVERSITY
O F \\‘ISCONSIN]
Relation between Precursor Structure and Biosynthesis of Penicillins1 Bs DONAI,D C. MORTIMER~ AND MARVIN J. JOHNSON RECEIVED APRIL 19, 1951 T h e addition of v:irious carbosylic acids to synthetic-medium fermentation of Penicillium chrysogenum Q176 brought about the synthesis of the corresponding penicillin if the acid added was not substituted in the a-position. The paper chromatographic assay for penicillin types showed thnt in the presence of sorbic, cyclohesaneacetic and phenoxyacetic acids, the percentage of precursor-prndnced penicillin was as high as in the presence of phenylacetic acid. The over-all precursor efficiency of these acids v a ~ however, , much l o w r than that for phenylacetic acid. The rate of metabolism of certain precursor acids 1i:is been found t o Rear a n inverse relation to precursor rthiency. -4cids substituted in the a- or (3- positions were not readily iiietabolized hy the mold. If a rapidly nieta1,olized acid such :I$ rorllic w a s acldecl t o the feririentatiuii a t frequent interv:ili, i:, precursor eific ieiicy Iiecanie comp:iral>lc15 it11 t h a t for the sloivly inetnbolized phenylacetic acid.
lhritig the early cooperative iiivestigatioris on ~~eiiicillin~ work was done in many laboratories on biosynthesis of penicillins. A large number of compounds were tested as possible precursors. It was found that when any one of a number of carboxylic acids ’ivas added to the fermentation, as such or as a suitable derivative, a penicillin was produced which was a substituted amide of the :i.citl added, just as benzyl penicillin is a substituted aniide of phenylacetic acid. Eleveti new penicill i were ~ crystallized. Later, Behrens and cowvurkersJs5reported tests on further possible ])re(‘ursors, ant1 isolated 1s additiotial new penicillins. .in additional five iiew penicillins were reported by Philip and others.6 At the time inost of this work was doiie, convenieiit criteria for production of new penicillins were not available. Stimulation of yield and variation of the penicillin activity ratio as measured on two test organisiiis were the methods used. After the advent of convenient paper clirorriatographic techniques, Thorn and Johnson’ were able to show that the lower saturated fatty acids regularly produced biosynthetic penicillins, :dthough such compounds had given no evidence of precursor activity in previous work. (1) Published with t h e approval of tlie Director of the \Visconqin Agricultural Bupt‘riinrnt Sintion. S u p p o r t e d in p a r t b y grunts f r o m hIerck a n d C o m p a n y , I n c . , Rahiray, h7..i , a n d from Chas Pfizer arid C o m p a n y , Brooklyn, N. Y. (2) Division of Applied Biology, Hatiolial Research Council, Ott a w a , Canada. (3) 0. K, Behrens, in €€, T. Clarke, J R. Johnson a n d R . Robinson, ” T h e Chemistry of Penicillin,” Princeton CJniversity Press, Princeton, S J., 1989, p. 657, ( 4 ) 0 K. Behrens, J. Corsr, D . B I l i i f f . R G Jones, Q F.Soper a n d C. CI:. Whitehead, 1,Bid. Chem., 176. 7 i l (1918). ( 5 ) 0 . K. Behrens, J. Corsr, J. P. E d w a r d s I-. Garrison, I
