Bioinorganic Chemistry

8 Biochemistry of Group IA and IIA Cations R. J. P. WILLIAMS

Downloaded by MONASH UNIV on August 26, 2015 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0100.ch008

Oxford University, Oxford, England

The biological function of Group IA and IIA cations of the periodic table is reviewed against the background of their chemistry. Utilization of these cations arises from an ability to form different types of complex compounds, which is dependent upon the radius-ratio effect. If the details of their biochemistry are to be understood, new probe methods for following the cations in biological systems must be devised. Some possibilities based upon the principle of isomorphous replacement are described and tested. * " p h e chemistry of the Group I A and I I A series of cations is relatively easy to understand as all its features are discernible from an inspection of the ionic model for chemical bonding (1, 2). This model shows that i n an exchange reaction leading to a complex or an insoluble salt from a simple hydrate M(H 0) 2

n

+ L -> M L ( H 0 ) 2

m

+ (n -

m)H 0 2

different cation stability sequences can be generated depending on the nature of the ligand, L , even though L is a simple anion or ligand. If L is a very large anion (usually of a strong acid) then the orders are Cs+ > Rb+ > K + > Na+ > Li+

(1)

Ba + > Sr + > Ca + > M g +

(2)

and 2

2

2

2

which are sometimes called the lyotropic series. A clear-cut example is provided on association with sulfate anions either in solution or in the solid state but the orders are much more strikingly demonstrated in the solids where cooperative interactions are important. The opposite orders can be generated by simple small anions ( usually of necessity of a weak acid) such as hydroxide. Li+ > Na+ > K + > Rb+ > Cs+ 155 In Bioinorganic Chemistry; Dessy, R., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

(3)

156

BIOINORGANIC CHEMISTRY

and Mg + > C a


2

2 +

> Sr + > Ba + 2

(4)

2

In 1952 we proposed (3, 4, 5) that such changes in the free energy orders arose through a type of radius-ratio effect operating on the asso ciated systems in both solid and solution, salts and complexes, comparable with the effect discussed by Pauling in his book (6) in order to explain the melting points of alkali halide salts. According to the increasing degree of importance of the radius-ratio effect, Orders 3 and 4 change toward Orders 1 and 2 with the changing size of the ligand, and maxi mum stability can be achieved by any of the cations i n the two different groups as Orders 3 and 4 switch to Orders 1 and 2. Our discussion showed this by a consideration of the solubility of both the Group I A and IIA salts ( I , 2, 3, 4, 5 ) . Furthermore, when considering binding to multidentate ligands and anions, it is not only the chemical nature of the individual coordinating group which counts but more importantly the packing of the anions around the cations. Table I shows that simple carTable I.

Some Stability Constants for Group IIA Cations, logio Κ

Acetate Oxalate Glycine Imido diacetate Nitrilotriacetate EDTA EGTA* Sulfate (log K) (log S.P. Phosphate (log S.P. ATP Carbonate (log S.P. Football ligand a b

c

Mg*+

Co +

Sr*+

0.82 3.4 3.4 2.9 5.3 8.9 5.4 2.0 0.0 24.0 4.2 7.5 2.0

0.77 2.8 1.4 2.6 6.4 10.7 10.7 2. 5.0 27.5 4.0 8.5 4.1

0.44 2.5 0.9

2

Ba

i+

0.41 2.3 0.8 1.7 4.8 7.9 8.0

-

5.0 8.8 8.1

-

-

6.5 27.4 3.5 9.0 13.0

10.0) 22.5) 3.3 8.5) 15.0

C

Data from Ref. 7. EGTA is 2,2 -ethylenedioxybisethyliminodi (acetic acid) ; S.P. is solubility product data; ATP is adenosine triphosphate. Ref. 8. /

boxylates (weak acid anions) give Order 4 but complex carboxylates give an order between 2 and 4. Oxalate in solution gives Order 4 but the insolubility of oxalates follows the order C a > Sr > B a > M g , showing the increased influence of the radius-ratio effect in the solid state because of packing problems in a continuous lattice. While it was immediately clear that several different orders of the free energy of this exchange reaction could be generated for Group IIA cations both in solution and the solid state and for Group I A in the solid state, it was 2 +

2+

2+

In Bioinorganic Chemistry; Dessy, R., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

2 +

8.

Table II.

Some Stability Constants, log K, and Other Data for Group IA Cations

E D T A (log K) P 0 - (log K) Dibenzoylmethane (log K) N 0 - (log K) S 0 - (log K) Ring chelate X X X I (log K) Football ligand (log K) Substituted picrylamine anion (log extraction coefficient) 2

7

2

3


4

157

Group IA and IIA Cations

WILLIAMS

2

IÂ+

Na+

K+

Rb+

2.8 3.1 5.9 -1.0 0.6 0.0

1.7 2.3 4.2 -0.4 0.7 0.0 3.6 1.8

0 2.3 3.7 0 0.9 2.0 5.1 3.7

—

1.0

Ref.

-

-

2.3 3.4 0.1

3.5

-

-

1.5 3.7 4.2

1.1

-

5.2

7 7 7 7 7 12 8 18

not possible to demonstrate until recently (9,10,11 ) that several different orders could be generated i n solution for Group I A cations by the same radius-ratio effect. In particular, studies using series of organic cyclic ligands, Table II, have redirected attention to this size effect. This has led to the speculation that such cyclic ligands are the only organic ligands which can generate orders different from 3 in solution (9, 10, 11) as most known simple anions give this order. Table II shows that this is not the case, that large inorganic anions give Order 1 and that one large, organic, noncyclic anion can also generate Order 1, at least in the extraction of these cations into organic solvents. Intermediate orders are to be expected with different large anions (9, 10, I I ) . It is the authors' contention that all the different orders originate as a consequence of the effect of packing upon ionic interactions. The packing problem can be inspected initially through the study of structures. Since 1952, many crystal structure determinations have been carried out on the alkaline and alkaline earth salts. W e have summarized these elsewhere (14); they clearly show that while N a and M g are usually 6-coordinate, K and C a are usually 8-coordinate with the same ligands. In many salts, the cations N a and M g remained relatively highly hydrated compared with the salts of K and C a . These structural changes in the crystals immediately illustrate how packing could produce changes in the stability orders in accord with ionic model considerations. I shall therefore use the words radius-ratio effect to denote that such size factors have caused deviation from Orders 3 and 4 toward 1 and 2. [A different language is used by Eisenman ( 15 ) who describes ligands by their "fieldstrengths" and "effective field-strengths," but I believe that his quite independent approach really refers to the structural property of the ligand as well as the "charge density" (field strength) on a given atom, Eisenman has been extremely successful in using his empirical approach but much of his argument is cyclic, in that the apparent field strength is estimated from the order which it is designed to explain]. +

+

2 +

2 +

+

2 +

+

2+



158


More detailed inspection of the ionic model shows that the radiusratio effect as seen in stability series is not essentially linked to changes in coordination number or to changes in the relative hydration of the cations; such changes are but structural ways in which packing problems manifest themselves. Even with a fixed coordination number, the sta bility constants of a ligand exchange reaction can take on almost any order i n so far that a ligand or group of ligands may most effectively bind to any one of the cations. Steric hindrance w i l l then manifest itself in increased bond lengths over those expected on the ionic model, the increase being the greater the smaller the cation. This is seen clearly in the complexes of ring chelates (9, 10, 11, 12) and must be obviously true i n complexes of large molecules such as proteins which have very many possible ways in which they can generate steric fitting and mis fitting. As these stabilities are studied against the background of coordi nation to water—a small ligand which is able to adapt itself to any size of cation—there may be but one coordination number for all the cations with a given ligand but the rather inflexible "hole" which is generated by the ligand w i l l bind certain of them preferentially. Radius-ratio effects can become important in two circumstances, therefore: W i t h large anions when anion-anion and anion-water contact w i l l restrict good packing and w i l l lower stability with small cations and with multichelating agents of rigid structure when the hole size may be such that small cations can not make good bond distances with all the potential chelating groups or they have to use energy in altering the conformation of the ligand so as to make such contacts. A further factor enters magnesium chemistry, though it hardly ap plies to any of the other cations. It is not part of the simple ionic model. The high charge and small size of the magnesium ion allow it to polarize bases. This accounts for the relatively high affinity of magnesium for nitrogen bases such as glycinate (Table I ) , chlorophyll, and some dyestuffs (e.g., magneson). In the light of the above observations, we have divided ligands into four major groups as far as biological systems are concerned (Table III). Table III.

Possible Biological Ligands of d° Cations

Ligand Type

Order

Example

Strong acid anions — O S 0 - — O P ( O R ) 0 Weak acid anions — Ο Ρ 0 " P 0 ~ 3

3

2

2

4

3

—COr, co 3

Neutral oxygen groups Neutral nitrogen groups

2

Alcohols, ethers, peptides, and esters — N H , imidazole 2

1 and 2 A l l orders are possible, depending upon radiusratio considerations. Or ders closer to 3 and 4 with the simplest ligands M g + > all others Li+ > Na+ > K+ 2


8.


WILLIAMS

Table IV.

159

Calcium-Binding Compounds of Cell Walls

Living Systems

Binding Chemicals


Bones

Chondroitin sulfate Glycoproteins Shells and plants Pectic acids Celluloses (Galacturonic acid) Algae Alginic acid (mururonic acid) Fucoidin (polyfucose sulfate) Carragenin (polygalactose sulfate) It is important to know if such ligands are separated in various biological compartments for then this separation alone would divide the cations functionally. Probably the only important separation is that sulfonate residues are extracellular—le., part of cell walls—for much the larger part. Calcium in particular is associated with the sulfonated polysaccharides as expected from Table I, see also Table IV, and from its binding to strong acid anion exchange resins (3, 4, 5, 15). As has been stressed many times elsewhere, thermodynamic effects such as differential binding of cations to groups inside and outside cells are quite insufficient to explain the ionic distributions generally observed in biological systems. Ion Distribution

in Biology

(16)

Very generally, potassium and magnesium are accumulated in cells but sodium and calcium are rejected by them. Thus, the competition for ligands inside a cell is biased compared with that outside. This distribution is essential for life as it stabilizes the cell against osmosis, by rejection of sodium, and against internal precipitation of carbonate and phosphate, etc., by rejection of calcium. Once these two major prerequisites of evolution had been established by the pumping action of membranes, life could develop using all four cations. Evolution has led to the following major systems which utilize the cation gradients. (1) Use of calcium (a) as an external structure factor and (b) as a cofactor for extracellular enzymes. (2) Internal use of calcium as a trigger for structural changes. (3) Internal use of magnesium and potassium as (a) cofactors of enzymes and (b) stabilizers of internal structures. (4) Transmembrane potentials of especially potassium, sodium, and calcium. Under ( 1, a ) we include the formation of cell wall structures which became elaborated as shells, bones, and cellulose structures (Table I V ) .


160


Table V.

Extracellular Calcium Enzymes and Enzyme Precursors Enzyme or Enzyme Precursor

Function

Trypsinogen Peptide hydrolysis A r y l sulfatase Sulfate ester hydrolysis B. Sutilis protease Peptide hydrolysis Nuclease Phosphate ester hydrolysis Amylase Saccharide hydrolysis Prothrombin Blood clotting through peptidase action


Table VI.

Possible Probe Ions for Substitution

Native Cation

Substitution"

a

Na+(0.95) K+(L33) Mg +(0.65) Ca +(0.99) 2

2

1

Li+(0.60) (poor) Tl+(1.40), Rb+(1.48), Cs+(1.69), NH +(1.45) Mn +(0.80) to Zn +(0.65) Eu (1.12), Mn +(0.80) La +(1.15) to Lu (0.93) U 0 ( ^ 1 . 1 ) etc. 4

2

2

2+

2

3

3+

2

a

2 +

Ionic radii are in parentheses.

Under (1, b) there are many extracellular enzymes of the digestive systems of species ranging from bacteria to animals (Table V ) . Under (2) we include release mechanisms for hormones and synaptic transmitters; the basic step of nerve transmission may be owing to calcium entry. Muscle contraction, movement of cilia, and many other dynamic structure changes are calcium-induced. (Perhaps cell division is another one of these processes?) Under (3, a) we include the activation of adenosine triphosphatases, the main energy sources of biology, and the possibility of control of a vast range of intracellular enzyme reactions, including those of glycolysis. Section (3, b) refers particularly to the stabilization of ribosomes and therefore to the control by magnesium and potassium of the whole of protein synthesis. Again, without magnesium and potasTable VII.

The Effect of Thallium on Biological Systems

Diol-dehydratase Pyruvate kinase Phosphatases N a / K ATP-ases (K-function) Erythrocyte transferases Muscle excitation ° Efficacy is a product of maximum velocity and



8.

WILLIAMS


161

sium, the synaptic junction fires spontaneously so that these cations also stabilize the vesicular systems which calcium destabilizes. Section (4) refers to the restrictions imposed on cation movement by membranes. The relative ease of movement of potassium through a nerve membrane at rest generates a potassium potential. Imposition of a perturbation upon the membrane changes its properties so that it is more permeable to sodium, and the activated membrane shows a sodium potential of reversed sign to the potassium potential. Thereupon a selfpropagating spike of depolarization which is rapidly followed by recovery to the rest state flows along the nerve cell and is the nerve message. It should be clear from the above and from recent summary papers of myself and Wacker (16, 17) that the biochemistry of the Group I A and I I A cations is exceedingly exciting. Inorganic chemists need to think how they can study this chemistry. Here I shall present our views on the possibilities of using series of related cations relying upon our knowledge of their chemistry and isomorphous replacement for K , M g , and C a by special probe cations. W e are attempting to understand not only the separate actions of the four cations N a , K , M g , and C a in enzymes but also their selective concentration and competition in membrane transport. A list of possible metal ion substitutions is given in Table V I . +

2 +

2 +

+

+

2 +

2 +

Probes for Group IA Elements Sodium is unlike any other cation in its charge and radius. Thus, sodium must be followed by its own nuclear properties (18). Potassium can be replaced, in principle, by thallium(I) and cesium. Both are useful as they have suitable nuclei for N M R studies but thallium has additionally an absorption band at 214 nm which is very ligand-dependent, a readily observable fluorescence, and a small temperature-independent paramagnetism which can cause marked shifts in the nuclear resonances of ligand nuclei. W e (19) have aimed in the first instance to discover if thallium replaces potassium effectively in enzymes. Table V I I shows that it does. Several Enzymes and Other Biological Systems Order of Cation Efficacy* T1+ T1+ T1+ T1+ T1+ T1+

> N H + > K+ > Rb+ > K + > Rb+ > Cs+ > > K + > Rb+ > Cs+ > > K+ > Rb+ > Cs+ > moves with K + > K + > Na+ Li+ 4

> Cs+ > Na+ > Li+ Na+ > Li+ N H + > Na+, Li+ Na+ > Li+ 4

Ref. 20 21 22,23 24,25 26 27

stability of binding in the various processes.


162


Thallium binds ten times more strongly than potassium to at least four enzymes and is equally effective as a catalyst. W e have therefore looked at the stability of binding of thallium as compared with potassium to various ligands. W i t h neutral ligands such as ether-oxygen, thallium and potassium binding are rather similar (R. M . Izatt, personal communication ) but an anion such as a single phosphate, ROPO3 ", or a carboxylate, —COo", binds about ten times more strongly, Table V I I I . W e conjecture, on the basis of this evidence alone, that K ( T l ) in enzymes may bind at a mono-anion center, sometimes phosphate and sometimes carboxylate, but that the "hole" size closely matches the radius of these two cations, 1.4 Â. In order to prove this assertion, we need crystal structure data on the thallium site, or, failing this, spectroscopic data. In Table V I I I we show that carboxylate and phosphate shift the absorption band of thall i u m ^ ) , and it is known that they quench its fluorescence. Using proton N M R , the T1(I) ion shifts acetate protons of E D T A by —0.21 ppm and ethylenic protons by —0.17 ppm relative to the parent anion. The examination of T1(I) phosphate complexes have shown that phosphorus resonances are shifted as follows relative to the respective parent anions: for pyrophosphate, —1.4 ppm; for adenosine triphosphate, «-P —0.5, β-Ρ —2.2, γ-Ρ —1.0 ppm; for adenosine diphosphate,

Bioinorganic Chemistry

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