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Biochemical and Clinical Problems in Molecular Genetics.

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the total amount of chromium present. The amount of
fluoride was determined using triphenyltin chloride.
Results:
a) Ratio CrvI: total Cr
Found 2:3.04; 2:3.00; 2:2.94. Calc. 2:3.
b) Total Cr : total F
Found 1:6.16; 1:6.40; 1:6.25 [2]. Calc. for CrF6 1:6.
c) For CrF5
Found C r : F = 1:4.98; 1:5.10. Calc. for CrFs 1:5.0.
Elemental fluorine was also detected qualitatively during the
decomposition of CrF6.
Further investigations are in progress.
Received, March 15th. 1963
[Z 468/297 IE]
[I] H . v. Wartenberg was the first l o obtain CrFs, albeit in very
small amounts: Z. anorg. allg. Chern 247, 135 (1941); 249, 100
(1942).
121 The sample contained traces or HF as an impurity, which
could not be removed.
C O N F E R E N C E REPORTS
Biochemical and Clinical Problems in Molecular Genetics
The Deutsche Akademie der N a t u r f o r s c h e r LEOPOLDINA organized this symposium on
January 26th and 27th, 1963 in HallelSaale (Germany)
On the first day, problems relating to the role of genetic
information in protein synthesis in the cell were dealt with.
The lectures on the second day were devoted to clinical
problems. It was shown that advancing knowledge of molecular reactions inside the cell provides insight into the
pathogenesis of hereditary diseases and in this way leads to a
rational therapy.
The Concept Scheme of Molecular Genetics
M . Delbruck, Berkeley, Calif. (U.S.A.) and Koln (Germany)
Molecular genetics attempts to explain the events of heredity
on the basis of molecular transformations. T o facilitate a
better understanding of the lectures on special problems
relating to the formation of specific protein molecules, the
following concepts were clarified:
Storage of information in deoxyribonucleic acid (DNA) by
means of a definite arrangement of nucleotides (triplet code);
the importance of the structure of D N A as a double helix formed by intertwining of two polynucleotide chains and
stabilized by hydrogen bonding between the purines and
pyrimidines of the two chains - for the replication of D N A
and for the relaying of information to messenger ribonucleic
acid (m-RNA); juxtaposition of the m-RNA, the matrix for
the protein molecule that is to be formed, and the transfer
RNA's, which conduct the amino acids to the site of protein
synthesis by means of hydrogen bonding between the bases.
An anticodon in the transfer R N A must correspond to a
codon in the m-RNA.
It was pointed out in the discussion that during the replication
of DNA, the double helix need only be partially unwound.
It is not yet known how the ver) long strands of the nucleic
acid molecules are handled by the cell.
The Role of the Cell Nucleus in Protein Synthesis and
Morphogenesis
J . Brachet, Brussels (Belgium)
In amoebae and Acetabularia, the formation of both m-RNA
and ribosomal R N A is dependent on the nucleus, since their
synthesis ceases immediately after removal of the nucleus.
Migration of nucleus R N A into the cytoplasm was demonstrated by labelling experiments. The source of the transfer
R N A is still unexplained, as is the question whether chloroplast R NA increases autonomously.
In connection with this problem, the question whether the
chloroplasts contain D N A was discussed. It was demonstrated by autoradiography in Professor Mothes' Institute
that thymidine is incorporated into dividing chloroplasts in
Angew. Chem. internat. Edit.
Vol. 2 (1963) No. 5
young, growing leaves, but not into those of old, fully-grown
leaves. The experiments show that the chloroplasts contain
D N A that takes part in some metabolic process. It is thus
possible that DNA-dependent, nucleus-independent RNA
synthesis occurs in chloroplasts.
The nucleus influences protein synthesis indirectly, since in
Acetabularia the quantity of protcin produced only decreases
three weeks after removal of the nucleus. m-RNA seems,
therefore, to have a considerably longer life-span in Acetabu[aria than in bacteria.
The m-RNA seems to influence morphogenesis, since this
process ceases in anucleate halves of Acetabularia after
RNase treatment, and is inhibited in nucleate halves by
actinomycin. However, it has not been elucidated whether
the morphogenetic substances are identical with the m-RNA
or with a specific, RNA-controlled protein.
The experiments with dividing amphibian eggs demonstrate
the importance of an RN A gradient for the differentiation
of the egg.
The Morphogenesis of Phages and their
Genetic Determinants
E. Kellenberger, Geneva (Switzerland)
The stages of phage synthesis can be ascertained by inhibition with specific inhibitors or by examining mutants.
Examination of T4 mutants showed that at least 50 genes are
necessary for the development of the phage. Two groups of
genes are distinguished and their arrangement on the chromosomes determined:
1. Genes for the synthesis of thc DNA and
2. Genes for the synthesis of the phage proteins.
Smaller groups within these principal groups comprise genes
whose function concerns the same phage component.
Mutations that block the synthesis of phage-DNA prevent
all the genes of the second principal group from functioning.
Electron micrographs showed phage fragments that had
arisen after blocking of part reactions.
The Chemistry and Biochemistry of Soluble
Ribonucleic Acid
H . G'. Zachau, Koln (Germany)
Transfer-RN A has the function of conducting activated
amino acids to the m-RNA in such a way that the amino
acids become attached in an ordered arrangement to the
growing peptide chain. It is assumed that m-RNA (matrix)
and transfer-RNA (adaptor) are attached to each other in a
specific manner by hydrogen bonding between nucleotides
267
(triplet code). In order to be able to analyse that portion of
the transfer-RNA molecule (anticodon) responsible for the
attachment, the transfer-RNA specific for each amino acid
must be isolated from the mixture of soluble RNA's, for
instance by countercurrent distribution of the tri-n-butylammonium salts of the R N A's. After fermentative cleavage
of the purified RNA's, their cleavage products can be
separated chromatographically and their nucleotide components determined. However, it has not yet been possible
to arrange the fragments, so that the structure of the
anticodon is still unknown. The structure for enzyme
recognition that must be contained in the transfer-RNA is
also unknown. Further unsolved questions are: are there
twenty or more transfer RNA's and what is the source of the
specificity of the transfer-RNA?
Ribosomes and the Molecular Mechanism
of Protein Synthesis
A . Gierer, Tubingen (German)) (communicated by
H. G. Zackau)
Optimal conditions for synthesis of a protein are only present
when several s 7 0 ribosomes are bound together by m-RNA
into particles of approx. S = 150 (S = sedimentation constant). Even after the addition of synthetic ni-RNA, these
aggregates show no increase in amino-acid incorporation.
In the discussion, a question was asked about the function of
ribosomal RNA. It must not be assumed that it only possesses
carrier function and is otherwise inert, since it is clear that a
given m-RNA becomes associated with only certain ribosomes.
On the Experimental Analysis of the Amino Acid Code
J. H . Mutfhaei, Tubingen (Germany)
The sequence of always three nucleotides in m-RNA furnishes
the code for the sequences of amino acids in polypeptides.
Investigations with mutants prove this. The function of the
matrix can be demonstra ed in a cell-free system, to which a
new m-RNA (virus RNA or polyuridylic acid) is added in
vitro. In this way, it was possible to obtain information o n the
coding for amino acids using synthetic polynucleotides as
m-RNA. It is not yet known from which end of the polynucleotide chain the code shou:d be read off. Experiments in
which trinucleotides were incorporated into m-RNA or were
polymerized by polyphosphates by the method due to
Schramm might be expected to shed light on this problem.
It may be assumed that not all codons can exist in neighboring
positions. Neighboring bases certainly have some influence
o n each other.
I n the discussion, Prof. Wacker, (Prankfurt/M.) pointed out
that m-RNA that contains bromouracil instead of uracil is
inactive. A code consisting only of purines is resistant to
ultraviolet irradiation, while a pyrimidine code is altered by
this treatment.
Studies on the Biosynthesis of Tobacco Mosaic Virus
G . Schramm, Tubingen (Germany)
Biosynthesis of the virus requires 30 hours. The chronological
sequence of events in this process is: 1 . 5-10 h : IiberaLion
of the RNA, 2. 10-15 h: grouth of the RNA, 3. 3-5 h :
growth of the protein, and 4. 5-8 h: production of the highmolecular-weight protein. It has not yet been elucidated
whether the RNA synthesis requires the presence of D N A
as a primer, or whether the R N A itself can act as primer.
The isolation of a n RNA polymerase from tobacco leaves
makes it possible to carry out an experimental examination
of this point. Under the influence of the polymerase, a
mixture of purine- and pyrimidine-triphosphates (ATP,
GTP, UTP, CTP) is converted principally into oligonucleotides with sedimentation constants S = 1.0-1.5. Only about
268
0.2% of the reaction product has a higher molecular weight
and is found in the same fraction as TMV-RNA. The content
of polymerase is the same in healthy and in TMV-infected
leaves. TMV-RNA is destroyed by polymerase from healthy
leaves on account of its RNase content. However, TMV-RNA
that is mixed with polymerase from infected leaves is not
degraded but, o n the contrary, increases in activity. On the
basis of these results, attempts can be made t o prepare an
informative RNA in vitro.
Polynucleotide Synthesis in Coacervate Drops
A . I. Oparin, Moscow (SSSR)
Polymers such as polypeptides or polynucleotides can
associate together to form complexes, which are demarcated
from the exteriial medium but which enter into reciprocal
exchange with the surrounding solution and which selectively
absorp material from it against concentration gradients.
According to Oparin, during the course of terrestrial history,
corresponding coacervates were subjected to selection, which
led to adaptation to environmentalconditions and to evolution
of complex systems. These complexes had to be self-reproducing.
Experiments have shown that RN A in a coacervate drop is
broken down by RNase and that a coacervate drop containing polynucleotide phosphorylase abstracts ADP from
the external solution and converts it into polyadenylic acid.
In the discussion, Prof. Schramm pointed out that the
formation ofthe first matrix is the decisive factor in the origin
of self-propagating complexes and thus for the possibility of
evolution. In his studies on non-enzymatic syntheses of
nucleic acids, it had been shown that polyadenylic acid can
act as a matrix and accelerate the formation of polyuridylic
acid and vice versa. The basic question is therefore: how has
the information entered into the macromolecules?
The Molecular Structure of Haemoglobin and
its Modification
C. Braunitzer, Munich (Germany)
The primary structure (amino-acid sequence) of human
haemoglobin has been completely elucidated. The secondary,
tertiary, and quaternary structures have been examined by
means of X-ray analysis, which has made it possible to derive
relationships between the amino-acid units and the spatial
construction. The a- and @-chainsof haemoglobin and the
myoglobin chain all show great similarities in spatial construcrion, although, in the helical regions, numerous amino
acids are not possessed in common by the several chains and
are therefore not interchangeable. However, some amino
acids occupy the same positions in all chains. Proline is
generally present where there are kinks in the chains.
If only one amino acid in tbe a- or @-chainof haemoglobin is
exchanged for another, an anomalous haemoglobin is formed
that gives rise to symptoms of disease. Thus, in the @-chain
of sickle cell haemoglobin, for instance, glutamic acid has
been replaced by valine. If a cysteine is oxidized at the site far
away from this glu-val exchange, then sickle cells d o not
arise. No explanation has yet been deduced for this behaviour.
By means of the model, it can be seen that the oxidizability
of the iron in the haem is altered by exchanging histidine for
tyrosine and valine for glutamic acid at a certain position in
the chain but not, on the other hand, by replacement of
histidine with arginine.
The Pathological Importance of HaemoglobinAnomalies
K . Betke, Tubingen (Germany)
Haemoglobin anomalies are gene-dependent. The pathological symptoms generally become apparent only when the
anomaly is inherited homoiygously. Normal human haemoAngew. Chem. internat. Edit. [ Vol. 2 (1963)
I No. 5
glohin consists of > 95 % HhA, 2 % HbA2, and 0.5 % HbF.
This composition is altered by anomaly of the a- or @-chains
in HbA, since as a replacement for the defective chains, 6
(HbA2) and y (HbF) chains are incorporated. Pathological
manifestations can he associated with definite changes in the
composition of the haemoglobin.
Biochemistry and Pathogenesis of Hereditary
Haemolytic Anaemias with Enzyme
Defects in the Hexose Monophosphate Cycle
G . W . Lohr and H. D . Waller, Tiibingen (Germany)
There are two haemolytic anaemias that are caused by
enzyme deficiencies in the hexose monophosphate cycle:
1. Glucose-6-phosphate dehydrogenase deficiency, the most
frequent hereditary disease. The life-span of the erythrocytes
is shortened. In general, haemolysis only occurs after ad.
a derivative of 8ministration of drugs ( e . ~primaquine,
aminoquinoline).
2. Glutathione reductase deficiency, first observed 1961/1962.
The haemolytic crises appear spontaneously.
Metabolism in Hereditary Enzymopathies
F. Linnewelz, MarburgILahn (Germany)
The following diseases due to enzyme defects were discussed :
1. Phenylketonuria: Blocking of the breakdown of phenylalanine to tyrosine leads to excrction of phenylpyruvic acid.
Since the amino acid pool becomes unbalanced as a result
of an excess of intact phenylalanine, resorption in the gut is
decreased. For this reason, the supply of essential amino
acids to the brain is reduced, this in turn leading to mental
deficiency if it occurs during the phase of brain differentiation
in the infant. By administration of a diet low in phenylalanine in the first year of life, such children could develop
normal intelligence.
2. Cystinosis is due to disturbance of the breakdown of
cysteine to taurine and the toxic: effect of the intermediate
product o n the kidney.
3. Leucinosis: The lack of a decarboxylase prevents catabolism of leucine, isoleucine, and valine.
4. Glycogenosis: There is a deticiency of glucose-dphosphatase.
[VB 687/79 IE]
Kinetics of the Thermal Decomposition
of Magnesium and Calcium Carbonates
The pressure dependence of k can be written:
E. Cremer, Innsbruck (Austria)
This relationship can be deduced from the same factors as with
the decomposition of CaC03, but with the assumption of
stronger COz adsorption.
[GDCh-01 tsverband Frankfurt/Main (Germany),
February 7tb, 19631
[VB 685/75 IE]
The rates of decomposition of MgC03 [l] and CaCO3 [2]
are strongly dependent o n the COz pressure, even in a temperature and a pressure range in which the reverse reaction
could certainly not yet be observable. The oxides had to be
decomposed at constant pressure in order to determine the
“order” of the reaction. The concept of order in heterogeneous reactions, however, poses certain problems. What
one measures here is generally the change of percentage
conversion (u) with time, and the equation
-d(lOO--u)/dt
k = k’ (1 + bPC0z)/PC02
Unimolecular Reactions in
Photochemical Systems
G. B. Porter, Frankfurt/Main (Germany) [4]
= k(100-u)”
applies formally, just as for gas reactions. For a gas reaction
however, (100-u) is proportional to the concentration in the
entire reaction volume, whereas for the heterogeneous
reaction, generally only a fraction of (100-u) % may have
the opportunity of reacting simultaneously. If the reaction
rate is proportional to the surface area of the starting
material, as is the case with CaCO3 prepared from CaO and
COz [2], then n = 2/3 in the above reaction. The data from
measurements of the decomposition of MgC03 are better
evaluated by a diffusion formula (for low conversion u2 =
kt) [l]. However, the diffusion through the oxide film formed
is certainly not rate determining [3]. The rate coefficient k,
which is independent of the degree of decomposition, can he
used to evaluate the pressure and temperature dependence of
the reaction. The induction period due to the formation of
reaction nuclei observed in the decomposition of CaC03 can
be eliminated by preforming the nuclei during preparation.
For the pressure dependence of the CaO formation reaction
a t 800-85OOC we have,
k = k* (l/Pcoz-~/Px)
This relationship can be derived theoretically if the estahlishCaO* + COz is
ment of a surface equilibrium CaC03
assumed, where px denotes the equilibrium pressure above
the reacting mass. The equilibrium pressure with MgC03 is
so high at 500-600°C that the term l/px can be neglected.
+
[I] E. Cremer, K . Allgeuer, and W. .4schenbrenner, Radex-Rundschau 1953,494.
[2] W. Nitsch, Ph. D. thesis, Universitat Innsbruck 1959; E. Cremer and W. Nitsch, Z. Elektrochem., Ber. Bunsenges. physik.
Chem. 66,697 (1962).
[3] L. Bachmann and E . Cremer, Z. anorg. allg. Chem. 6 5 , 309
(1961).
Angew. Chem. internat. Edit. 1 Vol. 2 (1963)
1 No. 5
Our studies of the dependence of pressure, temperature, and
wave length of the quantum yields of photolysis of gaseous
hexafluoroacetone show that there are two alternative
primary processes. One involves monomolecular dissociation
of excited singlet state molecules, which are formed with
vibrational energy considerably in excess of the equilibrium
energy during the excitation process with light. The fact that
the quantum yields decrease with increasing pressure can be
interpreted in terms of competition between dissociation and
collisional degradation. The quantum yields also decrease at
long wave lengths, because the excited singlet molecules are
formed with low vibrational energy. The temperature of the
system has little effect on this primary process, since it affects
only the equilibrium vibrational energy of molecules.
The second primary process entails unimolecular dissociation
of triplet state molecules formed from excited singlet state
molecules by intersystem crossing in a radiationless transition. Since the triplet state has a relatively long lifetime
(ca. 10-4 sec) there is ample time for vibrational equilibrium
to be established. Thus, this primary process is essentially a
thermal unimolecular reaction. As such, its rate constant
depends strongly on temperature, hut not on the wavelength
of excitation. Added biacetyl accepts energy efficiently from
hexafluoracetone triplet state molecules, completely deactivating them to the ground state. Even traces of biacetyl eliminate
the second mode of dissociation almost completely, which
permits the two primary processes to be studied independently.
[GDCh-Ortsverband Freiburg-Stidbaden (Germany),
[VB 686174 E l
February 8th, 19631
[4] Present address: lnstitut fur physikalische Chemie der Universivat Frankfurt/Main. Work carried out in collaboration with
P . Bowers, University of British Columbia, Vancouver (Canada).
269
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