We owe our initial understanding of enzyme substrate interaction to the genius of the great German organic chemist Emil Fischer, who came up with the idea of a specific receptacle like structure into which the analogous shape of a substrate fits structurally. The pair fit like a lock and its key. This precise alignment of the key markings and shape, fit and permit the turning of the tumblers to unlock. He even took the analogy further by comparing the phenomenon of competitive inhibition by a drug or substance to a key which fits the lock but does not open it, thus rendering the lock inaccessible to its natural or preferred substrate. This led to a systematic search and discovery of a variety of enzyme inhibitors to block specific key enzymes.

Sulfa drugs inhibit an enzyme necessary for a component of bacterial DNA. AZT inhibits a viral enzyme used by a replicating HIV virus. Penicillin inhibits an enzyme making the bacterial cell wall. Finasteride molecule resembles the testosterone molecule and blocks the enzyme Type Two 5-alpha reductase,, which converts testosterone to dihydrotestosterone the active version of the male hormone responsible for enlargement of prostate and some prostatic cancers in older individuals. It is used for treating prostatic hyperplasia under its trade name Propecia. The newest anti-cancer drug for metastatic prostatic carcinoma  Abiraterone, blocks the enzyme 17-hydroxylase, which is involved in the synthesis of steroid hormones at an even earlier stage in the testes as well as the adrenals. Angiotensin Convertase enzyme inhibitors are used to treat hypertension. 

A Dendreon Pharmaceutical drug Provenge (Sipuleucel-T) is a white cell infusate artificially activated in vitro to directly attack prostate cancer cells specific to a individual patient. The treatment costs 93,000 dollars and increases average life expectancy by four months. Avastin, Herceptin,Yervoy are other cancer drugs each costing tens to hundreds of thousand dollars per patient approved for payment by Medicare, which is prohibited by law from any negotiation of costs or factoring cost in any form as a measure of payment approval. No wonder the US is headed for bankruptcy and the Republicans want to cut Social Security which has minimal funding deficits, Medicare with large looming deficits and yet increase defense spending and give more tax cuts to their rich campaign contributors.

There is a somewhat far fetched analogy between competitive inhibition of enzymes to bring about a desired medical outcome and occupation of key strategic harbors and bases (see my article on Colonies & Bases). The earliest parallel is the foreign policy of Athens before the Peloponnesian War. They sent envoys to various Greek islands in the Aegean Sea, including Sparta’s allies (See my article on “A History Of International Relations) to wean them from their alliance to Sparta and make them Athen’s allies and tribute paying protectoratesa (like Mafia policy of protection money which we demand from Gulf States and now Libya). Athens wanted to occupy Melos and dominate the Cyclades and Southern Aegean. During WW2 the Axis powers occupied Crete, Lampedusa & Corsica to dominate the Mediterranean, while Britain and the allies held Malta and Cyprus. Japan went for the Pacific islands. These occupations were a form of competitive inhibition to lock out the control of the opponents. It also explains the US interference in Cuba in the Spanish American War with resultant occupation of Guam, Philippines, Puerto Rico and Guantanamo Bay in Cuba. 

It also explains why the Portuguese built forts at Angola, Mozambique, East Timor, Ceylon, Goa, Bombay, Daman, Diu and Socotra to dominate the Indian Ocean and Macao to dominate the South China Sea. To compete the Dutch went to South Africa and Indonesian islands, even to New York (known before as New Amsterdam). The French took parts of West Africa, Seychelles, Mauritius and Djibouti, Cambodia and Vietnam. The British overtook the others by getting Sierra Leone, Nigeria, South Africa, East Africa, Ceylon, India, Gulf Sheikhdoms, Aden. The British first started with fortified trading posts and forts in Madras, Surat etc., but eventually went from the competitive inhibition of Finasteride to the cell toxicity of Provenge by inducing a regime change as they did in India beginning with Clive and Warren Hastings and continuing with their policy of annexation (as in Jhansi) or political agents to supervise the Indian Nawabs and Maharajahs. 

America has followed the British policy after it inherited the world from the dying British Empire, fatally wounded in trying to deny Germany its deserved seat at the power table. Earlier Germany had tried colonizing with genocide in Southwest Africa (with Herrero genocide) and East Africa but had to surrender its colonies after its defeat in WW1. During WW2 it chose the Russian method of contiguous land conquest, lost again, bankrupted Britain and has risen like a Phoenix by its sheer industry. So America keeps trying regime change by bribery or force in the entire Western Hemisphere, Middle East, South and Southeast Asia and even Kyrghyzstan, Ukraine, Georgia and fragments of Yugoslavia. Bases and regime change were used as refueling stations, for sea lanes domination, resource exploitation and by the British for military manpower when they dealt with people as stupid as those of the India. Why even today America, the copycat, offers citizenship to foreigners who enlist to fight its wars just as the French did in the Foreign Legion.

Nature and Evolution have found another way to move reactions in a favorable direction. If the auto sales figures go down severely the manufacturers have to stop the process at the very beginning. If they continue the assembly line to the last stage like painting the car, they will have to store and finance the excess inventory and spare parts. Such feedback control mechanisms are ubiquitous in biological and nervous systems where the end product which bears no resemblance to the enzymatic site or substrate serves as a feedback inhibitor to its own formation.
 
Jacobs and Monod (French scientists of Pasteur Institute) discovered this in the metabolism of glucose and lactose by E. coli. The enzyme to break down lactose is Beta-galactosidase and is not present in the bacterial cell. The gene responsible for making the messenger RNA to send to the ribosome, to make the enzyme protein, is normally repressed by another protein which attaches to the gene site on the DNA chain of the bacterium. As soon as its surrounding medium shows the presence of lactose and absence of its preferential diet of glucose, a lactose molecule diffuses into the cell and attaches to the repressor covering the beta-galactosidase gene site, but at a different part of the repressor protein than that which is attached to the gene site. This changes the conformational shape of the protein, which falls off the repressed site and allows the beginning of beta-galactosidase messenger RNA synthesis. 

The chemical structure of the protein is the same, only its folding or shape changes. This is how hemoglobin of our blood loads up oxygen in our aerated lungs and parts from it in oxygen deprived tissues which have a higher content of diphosphoglycerate from metabolism of glucose. DPG changes the shape of Hemoglobin, not its chemical composition. There is a whole bunch of substances called “G” proteins because they alter shape, depending on whether they are bound to Guanosine triphosphate or Guanosine diphosphate, which serve as signal transducers for a host of metabolic processes from energy production to cell differentiation, cancer and reproduction. Such signals can be instructive and energy consuming or they can be permissive and most, if not all are passive and permissive. They speed up the direction or reversal of the process dependent on what is necessary for survival and growth locally. This whole business becomes possible because a site on the protein removed and different from the catalytic site shifts the enzyme shape which is in a precariously balanced phase (like on a knife edge). Such weak linkages are energy efficient, rapid, environment sensitive and repeatedly used by living organisms. This property of proteins is called Allostery (allo meaning other, stereo meaning solid) by Monod, who without humility announced he had found the second secret of life. (first was Watson & Crick’s discovery of DNA)

Now allostery has been utilized in foreign policy by a different form of occupation or colonization. In 1493, the Pope who was of Spanish origin issued a Bull granting all lands which were few hundred miles west of Cape Verde Islands to Spain and the nearer ones to the east, to Portugal. Now you know where the word bullshit means! Of course Portugal found a way out to colonize Brazil. The Soviet Union used another variant of allostery to obtain subordinate allies in Asia and Africa. It appealed to newly decolonized third world nations by proselytizing its communist nature and anti-colonialism credentials, while hiding its contiguously expanding empire and its atrocities towards kulaks, Tartars, Chechens and others. These kinds of divinely acquired colonies or philosophically brainwashed neo-colonies are a form of exploiting allostery. The lesson for America to learn is, that allostery of allying with the native populations’ legitimate desires, aspirations and well-being transforms their politically active catalytic shapes to favorable, stable and persistent alliances in a permissive form without bribes, bullying or COIN strategies. Thus a combination of soft power, realpolitik and some principles are a better beacon to steer the ship of state, than short term alliances with despots who exploit, terrorize and tyrannize their populations.

Interested readers may wish to read Marc W. Kirchner & John C. Gerhart’s book “The Plausibility Of Life” and Monod’s book “Chance & Necessity”. Also the writings of Mearsheimer & Walt on foreign policy.

Next Week – US Foreign Policy, Wodehouse’s Freddie Widgeon & Tennyson