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J Med Biochem. 2015 July; 34(3): 271–281.
Published online 2015 July 14. doi:  10.2478/jomb-2014-0045
PMCID: PMC4922346

Language: English | Serbian

Curious Cases of the Enzymes

Neobična Istorija Enzima


Life as we know it heavily relies on biological catalysis, in fact, in a very nonromantic version of it, life could be considered as a series of chemical reactions, regulated by the guarding principles of thermodynamics. In ancient times, a beating heart was a good sign of vitality, however, to me, it is actually the presence of active enzymes that counts… Though we do not usually pay attention, the history of enzymology is as old as humanity itself, and dates back to the ancient times. This paper is dedicated to these early moments of this remarkable science that touched our lives in the past and will make life a lot more efficient for humanity in the future. There was almost always a delicate, fundamentally essential relationship between mankind and the enzymes. Challenged by a very alien and hostile Nature full of predators, prehistoric men soon discovered the medicinal properties of the plants, through trial and error. In fact, they accidently discovered the enzyme inhibitors and thus, in crude terms, kindled a sparkling area of research. These plant-derivatives that acted as enzyme inhibitors helped prehistoric men in their pursuit of survival and protection from predators; in hunting and fishing… Later in history, while the underlying purposes of survival and increasing the quality of life stayed intact, the ways and means of enzymology experienced a massive transformation, as the ‘trial and error’ methodology of the ancients is now replaced with rational scientific theories.

Keywords: enzyme, drugs, inhibitors, art, history, industry

Kratak sadržaj

Život oko nas uglavnom se zasniva na biološkoj katalizi, pa bi se čak, u nekakvoj neromantičnoj priči, život mogao opisati kao niz hemijskih reakcija koje regulišu glavni principi termodinamike. U davnoj prošlosti, kucanje srca bilo je znak dobrog zdravlja, međutim, za mene, najvažniju ulogu ima upravo prisustvo enzima... Mada ne obraćamo često pažnju na to, istorija enzimologije stara je koliko i sam ljudski rod i seže daleko u prošlost. Ovaj rad posvećen je baš tim počecima u ovoj veoma zanimljivoj nauci, koja je u prošlosti ostavila traga na našim životima i koja će u budućnosti učiniti da život bude mnogo produktivniji za čovečanstvo. Između čoveka i enzima postojao je oduvek jedan delikatan, suštinski važan odnos. Suočen s nepoznatom i neprijateljski nastrojenom prirodom punom grabljivaca, preistorijski čovek rano je otkrio lekovita svojstva biljaka, i to metodom probe i greške. Štaviše, slučajno su otkriveni inhibitori enzima, čime je, grubo rečeno, još tada otvorena nova oblast istraživanja. Ovi biljni derivati koji su imali ulogu inhibitora enzima pomagali su preistorijskom čoveku u njegovoj borbi da opstane i zaštiti se od grabljivaca; prilikom lova i ribolova... Kasnije kroz istoriju, sa nepromenjenom svrhom opstanka i poboljšanja kvaliteta života, enzimologija je iz korena transformisana, a metodologiju »probe i greške« iz praistorije zamenile su racionalne naučne teorije.


Life begins with a catalytic activity. The importance of catalytic activity was annotated by Kleczkowski and Garncarz (1) in a very striking manner, that is, ‘the original environment of life on Earth was seawater containing micronutrients with structural, metabolic and catalytic activity’. Today, we know that germination of spores begins with macromolecular synthesis (2).

Historical relevance of clinical enzymology begins with Francis Home in 1780, through his studies on the detection of glucose in urine (3). Catalysis per se as a term was first introduced by J.J. Berzelius in 1836 (4). Richard Bright, on the other hand, dedicated his work to the investigation of ‘proteinuria’ by heating up urine with a candle flame in a tablespoon (1789–1858) (5). After many subsequent works by the 19th century scientists, it became evident that digestion was in fact done by the relevant enzymes (6). Scientific enquiries in clinical enzymology began with rudimental tests, mostly performed haphazardly, and this later paved the way for more sophisticated methods such as nuclear magnetic resonance and mass spectrometry (5). Nowadays, moreover, there are myriads of different, equally fascinating areas of research on enzymes; diseases, metabolic significance, catalytic mechanisms, novel roles and interactions with various chemicals, drugs, agonists, metals are only a few of them… (715). Applications of computational protein studies give different points of view for investigation and designing novel catalysts from scratch. Through these delicate, meticulous approaches, clarification of protein-protein interactions and inhibitors of various molecules and large oligomeric assemblies is made possible (16). With the project ‘Enzyme Function Initiative’, defining sequence-structure interaction/interdependence would provide the prerequisite infrastructure for accurately predicting the in vitro functions of previously unknown enzymes and open the door for much more challenging studies (17). Both in the near and distant future, life might require and depend on designing state-of-the-art application areas of enzymes for novel scientific outcomes in daily life in addition to their benefits in medicinal therapies (1820).

Enzymes are Vital for Every Part of Life

With the limited evidence, the daily, monotonous life of ancient humans is hard to predict with precision, yet one thing known for sure is that they also required various food sources to sustain life. Based on the preexisting knowledge in addition to newly emerging data, we are putting pieces together and trying to predict and clarify which enzyme-bound products they used.

What was the role of fermentation in the emergence of enzyme products in the ancients’ life? In fact, was the first enzyme product a fermented one or not? Which came first? Bread? Wine? Vinegar? Beer? Soy sauce? Kumis? Sake? Koji? Kefir? Sour cream? Pickles? Sauerkraut? Sourdough? Yoghurt? Boza? Kimchi? Miso? Tempeh? Or perhaps a completely distinct, unknown enzyme product was consumed that unfortunately left the scene with no trace for us to follow.

Neanderthal man’s food culture began to emerge approximately in 30,000 BC with the introduction of bread (21) and, accordingly, it is very hard to find any documented evidence on this subject. Bakery technology begins with the cultivation of wheat in Göbekli Tepe that is, with its 11,600 years old existence, also the world’s oldest temple. Sourdough starters or yeast was used as a food additive in bread baking, however, the exact or approximate date is not clear (22). Dairy products were another important food source in ancient societies. Cheese is an effortless candidate to claim the role of being the first enzymatic product. And the use of milk dates back to 8,000 years ago and it evolved in the ‘Fertile Crescent’ between the Tigris and Euphrates rivers (23).

Koumiss was an alcoholic beverage (V century BC) of ancient times in central Asia and was used in the treatment of various diseases such as phthisis (24). Yogurt and kefir are also among the ancient traditional dairy products and were used extensively as preventive compounds against diseases, and for curative purposes. The nomads carried fresh milk in bags, probably crudely made from animals’ stomach, and the milk, in this relatively perfect condition, fermented into yogurt or kefir (25). The origins of wine and vinegar go back to as far as 2,500 BC. Hammurabi tablets, casted in stone, are perhaps the first documented artifacts on fermentation of grapes. These tablets date back to 2,100 BC and again this was probably the first document on the commercial use of enzymes. The second commercial product of the enzyme origin might have been vinegar, which was widely used in those days both for medicinal purposes as a painkiller, and in disinfection of wounds and finally in food storage (26). However, C. Wang and his colleagues, using five analytical methods to identify the chemical constituents of the potteries originating from China, found out that the emergence of various fermented products dates back to as early as 7,000 BC (27). On the other hand, the origin of sake is an oblique one. Sake may be as old as wine. It goes back as far as 2,500 years when the cultivation of rice became widespread. The most mysterious and acutely necessary component of sake is koji which contains alpha-amylase, beta-amylase proteases, peptidases, sulfatases enzymes. Traditionally, koji is also used in soy sauce and in miso. Natto is a traditional, dateless Japanese meal and the enzyme found in natto has been named nattokinase (28).

Smell or the occurrence of various odors, again an interesting façade of enzyme catalyzed reactions, is another, crucial factor in survival. The first study on enzymatic catalysis and the related occurrence of odors was performed approximately four decades ago. Investigators, for instance, studied the effect of γ-irradiation on cystein sulfoxide lyase and odor of onions (29). Odors originating from the catalytic activities of the enzymes are potent regulators of biological functions. Jasmonic acid, a highly volatile terpene compound, shows its effect on protein kinases or transcription factors (30). Odor evoked behaviors or social interactions show their effect on the enzymes such as flavin containing enzyme monooxygenase-3 (31). In the determination and approximate diagnosis of various health problems, dogs and cats smell some of the diseases such as cancer, epileptic seizures, and hypoglycemia (32, 33).

Meat tenderizer, which contains the enzyme papain, has been recommended for the treatment of bee (34) and fire ant (35) stings. It was also established that these meat tenderizers were safe and effective for patients with a phytobezoar (36).

Enzyme Inhibition

Medicine is a cumulative pile of interactions from the collective components of science, technology and human values, beginning from the ancient times (37). Poisons, in other words enzyme inhibitors, are widespread in plants and animals and they were used – and are still in use – for hunting as arrow poison, in fishing (38) or in even warfare (39). The history of enzyme inhibitors is as old as humanity (40). However, the very first documented experiment on enzyme inhibition was done on proteolytic enzymes with formaldehyde in 1899 (40).

Enzymes and Art

In his article, Irvine H. Page proclaims that ‘Scientific research is, in many ways, related to art’ (41). Enzyme inhibitors have special roles in the production and stimulation of artwork! The whole assumption might seem irrelevant and out of context, but the roads of enzymes and artifacts might effortlessly entangle. One of the known art effector molecules is Thujone, which is widely established as a severely neurotoxic compound. A few liver enzymes are responsible in the metabolism of Thujone; cytochrome P450 (CYP), CYP2A6, CYP3A4, and CYP2B6. Thujone inhibits gamma-aminobutyric acid A (GABA) receptor (42, 43). It was discovered that CYP2A6 is the key enzyme in the metabolism of Thujone in human liver (43). The most interesting and appealing point of Thujone is that it is present in the notoriously famous absinthe drink (42). A number of great artists and writers from the late 1800s used absinthe as a social drink, including Vincent van Gogh and Toulouse-Lautrec (44). There are also implications for the ailments of Vincent van Gogh that involve heavy absinthe consumption (45). Furthermore, another enzymatic product, ‘vinegar’, is the main subject of a beautiful painting in Rijksmuseum. As a matter of fact, Cleopatra’s knowledge of chemistry allowed her to win a bet over Antony (46).

Enzyme Inhibitors and their Effects on Warfare

In the Second World War (WW2), Nazi Germany used acetylcholinesterase inhibitors such as tabun, sarin, and soman as chemical weapons. And following this initial experience in war, widespread weapon development programmes have been initiated in the exploration of various neurophysiological and neurotoxicological chemical compounds (47). These types of studies have opened a new window on enzyme inhibitors such as medical treatment in poisoning with organophosphorus compounds (48) and provided new insights on the reactivation of acetylcholinesterases (49).

Enzyme Inhibitors and Cosmetic Beauty

Sirtuins are associated with cellular energy metabolism and the redox state of the cell through their interactions with multiple signaling and survival pathways. It is accepted that activation of sirtuins is a valuable therapeutic target against aging and age-related diseases, including the renal diseases (50). Aging has now been defined both as a cellular and molecular event. And sirtuin-activating and anti-glycation products are already being marketed by cosmetic and pharmaceutical companies (51). Botulinum toxin, likewise, is an enzyme that enters peripheral cholinergic nerve endings and specifically and selectively cleaves one or more SNARE proteins to induce paralysis (52). Most patients and physicians are using monotherapy by the botulinum toxin for a natural look that softens wrinkles for the upper face profile (53). Recent studies show that botulinum toxin has many other roles in medicine (54).

Enzyme Inhibitors as Therapeutic Compounds

As a rule, most of the drugs derived from food products show their effect on enzyme inhibition (55). Target-based drugs and identifying novel and safe chemotherapy targets with particular emphasis on the inhibition of key reactions in metabolic pathways are many a researcher’s dream (56). Understanding the role of enzymes in various diseases and their detailed mechanisms is among the important aims of the enzyme inhibition studies (57). Antibiotics were first defined by Selman Waksman in 1941. He initially described an ‘antibiotic agent’ as a microbe that antagonizes the growth of other microbes. With the initiation and discovery of many antibiotics of different classes such as penicillin, streptomycin, chloramphenicol, and tetracycline between the years 1945 and 1955, the dawn of antibiotics formally began (58). Likewise, Angiotensin Converting Enzyme Inhibitors are among the most common drugs which are widely prescribed for benign hypertension (60). Furthermore, inhibition of key, regulatory enzymes in lipid metabolism provides medicinal benefits as well. For instance, statins are inhibitors of HMG CoA reductase which have been used for treatment of high cholesterol. Another group of the enzyme inhibitors are used for treatment of obesity (61). Examining and characterizing the mechanism of actions for enzyme inhibition is one of the trending topics in biochemistry (62). From the regulation of respiration, pH balance, gluconeogenesis, ureagenesis, lipogenesis and Na+ retention; to the prevention of calcification, carcinogenesis, it is clear that enzyme inhibitors can be used for diverse therapeutic purposes (63) and this list could be extendible. Furthermore, enormous clinical success can be achieved with novel enzyme inhibitors in cancer therapy as well and every day, researchers are defining new drug targets for various, equally challenging diseases (65). On the other side of the medallion, pharmaceutical companies spend enormous amounts of money for clinical trials and marketing in novel drug development studies that use enzyme inhibitors (66). It is, thus, not hard to foretell that the current and future researchers will try to investigate novel drugs or modify preexisting drugs in new, alternative therapies for developing novel drug indications such as successfully eliminating seizures with little or no side effects (1012, 14, 6772).

Mapping the active sites of the enzymes began in the middle of the 1960s but designing drugs that interact with the active site is an important field in drug development (73). Kinetic or modelling studies provide us with the information on differentiating the active site and binding site of the enzymes, respectively. Enzyme research, or in other words biochemical research, today focuses on the molecular basis of biological processes and it applies especially to human health and diseases (80). Self-evidently, enzyme inhibitors will always be one of the dominating trends in drug development (7479).

Enzymes in Industry

In the beginning of the current century, more than 3000 different enzymes from different organisms have been identified and many have found their respective applications in biotechnology as well as in the pharmaceutical, chemical and food industries (127). In fact, enzymes effectively changed the applications and methods in industries (128). Half a century ago, studies that involved various microorganisms began on clots formed in spoiling milk. By the year 1933, on the other hand, enzymes in bread and bakery industries started to mature with the observations of Blagoveschenski and Sossiedov on wheat flour (129). And even today, one of the most important study subjects is designing novel biocatalysts for the relevant industries (130) (Table II).

Table II
Role of enzymes in industry.

Applications that eventually ended up being used for commercial purposes initially started with the study of enzymes in daily, routine life. An effortless example, vinegar, practically had many applications in the past such as pickling of various food products both for preservation as well as for culinary purposes; carpet cleaning or removing of stains from fabrics, and as a brightening agent in dishwashing or antipyretic in villages, in Turkey. However, vinegar is still in use for similar or almost the same purposes in modern life.

Today, enzymes and the related enzyme products have many roles in industries including but not limited to pharmaceutical and food industries; perhaps most importantly, though, in medicine, enzymes can be used as valuable biomarkers in the diagnosis and management of various diseases such as heart, lung, liver, muscle, bone, pancreas, hematology, genetic diseases and malignancies as well as applications in toxicology and forensic medicine. Besides their roles as biomarkers in medicine, there are also various other applications in medicine such as; medicinal digestive enzymes that are used for therapeutic reasons, determination of parental lineage (149), and in plastic surgery (150). Examples of the industrial applications (wine, beer, cheese, bread, cosmetics, detergents, textile) are given in Table II. Advances in the science and technology of enzymes will give birth to revolutionary progress in many distinct areas.


Enzymes braced their roles in pharmaceutical industry as diagnostic markers or therapeutic molecules, still a very vivid area of research in the field. Commercial, mass production of many consumer goods such as cheese is made possible by some enzymes. Similar to his prehistoric cousin who made cheese from the stomach of slaughtered animals, the modern man also uses the same enzymes to make this widely consumed, delicious dairy product, only in immobilized forms suitable for commercial use. Moreover, the food industry today relies on enzymes as well. Biological detergents containing specialized enzymes such as proteases, lipases and isomerases are widely used in consumer products. Mighty enzymes have accompanied us on our journey through history and clearly they will be with us in the future with myriads of novel and preexisting benefits.

Both from a macro and micro perspective, needless to say, enzymes played key roles in humanity as well as in the preservation of life quality for ordinary men in everyday life. Enzymes have sparkling roles in every part of our life, from an apoptotic cell on the verge of dying to the sustaining of delicate balances in metabolic pathways. In fact, enzymes solidly marked their footprints in diverse, sometimes interrelated, mostly distinct fields; medicinal therapeutics, warfare, art and food industry are among some of these fields... These small machines that have the potency to make enormous chemical reactions possible in sometimes less than milliseconds constitute the magnificent and marvelous building blocks of our cells. An insight into the history of enzymology enhances our knowledge and understanding of biochemistry. Research on enzymes has had a central indispensable role in the past, present and future of biochemistry in almost every aspect of life. Enzymes are cardinal contents of life and, therefore, exploration of the functions of enzymes and various biochemically uncharacterized proteins with undisclosed functions will continue in the experimental designs of future research. Both current and future scientists working in biochemistry will always resort to enzymes and the methods in enzymology in their pursuit of reliable, scientific remedies and solutions.

Table I
Analysis of the historiography of enzymes.


Conflict of interest statement

The authors stated that they have no conflicts of interest regarding the publication of this article.


1. Kleczkowski M, Garncarz M. The role of metal ions in biological oxidation – the past and the present. Pol J Vet Sci. 2012;15:165–73. [PubMed]
2. Setlow P. Summer meeting 2013-when the sleepers wake: the germination of spores of Bacillus species. J Appl Microbiol. 2013;115:1251–68. [PubMed]
3. Büttner J. Evolution of Clinical Enzymology. J Clin Chcm Clin Biochem. 1981;19:529–38. [PubMed]
4. Robertson JB. The Early History of Catalysis. Platinum Metals Rev. 1975;19:64–9.
5. D’Alessandro A, Giardina B, Gevi F, Timperio AM, Zolla L. Clinical metabolomics: the next stage of clinical biochemistry. Blood Transfus. 2012;10:19–24. [PMC free article] [PubMed]
6. Kohler RE. The Enzyme theory and the origin of biochemistry. Chic J. 1973;64:181–96. [PubMed]
7. Jovičić S, Ignjatović S, Majkić-Singh N. Biochemistry and metabolism of vitamin D. J Med Biochem. 2012;31:309–15.
8. Lazarević D, Đorđević VV, Ćosić V, Vlahović P, Tošić-Golubović S, Ristić T, et al. Increased lymphocyte caspase-3 activity in patients with schizophrenia. J Med Biochem. 2011;30:55–61.
9. Karaman K, Tirnaksiz MB, Ulusu N, Dincer N, Sener B, Gulmez D, et al. Effects of dexamethasone on ischemia reperfusion injury following pringle maneuver. Hepatogastroenterology. 2011;58:465–71. [PubMed]
10. Tandogan B, Guvenc A, Calis I, Ulusu NN. In vitro effects of isoorientin, forsythoside B, and verbascoside on bovine kidney cortex glutathione reductase. Int Chem Kinet. 2013;45:574–9.
11. Tandogan B, Sengezer C, Ulusu NN. In vitro effects of imatinib on glucose-6-phosphate dehydrogenase and glutathione reductase. Folia Biol (Praha) 2011;57:57–64. [PubMed]
12. Tandogan B, Kuruüzüm-Uz A, Sengezer C, Güvenalp Z, Demirezer LÖ, Ulusu NN. In vitro effects of rosmarinic acid on glutathione reductase and glucose 6-phosphate dehydrogenase. Pharm Biol. 2011;49:587–94. [PubMed]
13. Tandogan B, Ulusu NN. Comparative in vitro effects of some metal ions on bovine kidney cortex glutathione reductase. Prep Biochem Biotechnol. 2010;40:405–11. [PubMed]
14. Tandogan B, Ulusu NN. A comparative study with colchicine on glutathione reductase. Protein J. 2010;29:380–5. [PubMed]
15. Tandogan B, Ulusu NN. Inhibition of purified bovine liver glutathione reductase with some metal ions. J Enzyme Inhib Med Chem. 2010;25:68–73. [PubMed]
16. Khare Sagar D, Fleishman Sarel J. Emerging themes in the computational design of novel enzymes and protein-protein interfaces. FEBS Lett. 2013;587:1147–54. [PubMed]
17. Gerlt JA, Allen KN, Almo SC, Armstrong RN, Babbitt PC, Cronan JE, et al. The Enzyme Function Initiative. Biochem. 2011;22:9950–62. [PMC free article] [PubMed]
18. Roncada P, Piras C, Soggiu A, Turk R, Urbani A, Bonizzi L. Farm animal milk proteomics. J Proteomics. 2012;19:4259–74. [PubMed]
19. He H, Qin Y, Chen G, Li N, Liang Z. Two-step purification of a novel β-glucosidase with high transglycosylation activity and another hypothetical β-glucosidase in Aspergillus oryzae HML366 and enzymatic characterization. Appl Biochem Biotechnol. 2013;169:870–84. [PubMed]
20. Natarajan P, Ray KK, Cannon CP. High-density lipoprotein and coronary heart disease: current and future therapies. J Am Coll Cardiol. 2010;30:1283–99. [PubMed]
21. Tannahill Reay., editor. Food in history. New York: Three Rivers Press; 1973. p. 16.p. 68.p. 69.
22. Mithen SJ, Finlayson B, Smith S, Jenkins E, Najjar M, Maričević D. Göbekli tepe: An 11 600 year-old communal structure from the Neolithic of southern Jordan. Antiquity. 2011;85:350–64.
23. Fox PF, editor. Cheese: An overview Cheese: Chemistry, Physics and Microbiology. 2ed. Chapman and Hall; London: 1993. pp. 1–36.
24. Salimei E, Fantuz F. Equid milk for human consumption. Int dairy J. 2012;24:130–42.
25. Rosell JM. Yoghourt and kefir in their relation to health and therapeutics. Can Med Assoc J. 1932;26:341–5. [PMC free article] [PubMed]
26. Copeland Robert A, editor. Enzymes, A Practical Introduction to Structure, Mechanism, and Data Analysis. John Wiley & Sons, Inc; 2000. pp. 2–10.
27. McGovern PE, Zhang J, Tang J, Zhang Z, Hall GR, Moreau RA, et al. Fermented beverages of pre- and proto-historic China. Proc Natl Acad Sci USA. 2004;21:17593–8. [PubMed]
28. Bamforth CW, editor. Food, Fermentation and Microorganisms. Blackwell Science; Oxford, UK: 2005. pp. 143–153.
29. Kawakish S, Namiki K, Nishimur H, Namiki M. Effects of .gamma.-irradiation on the enzyme relating to the development of characteristic odor of onions. J Agric Food Chem. 1971;19:166–9.
30. Xu Y, Zhang Z, Wang M, Wei J, Chen H, Gao Z, et al. Identification of genes related to agarwood formation: transcriptome analysis of healthy and wounded tissues of Aquilaria sinensis. BMC Genomics. 2013;8:1–16. [PMC free article] [PubMed]
31. Li Q, Korzan WJ, Ferrero DM, Chang RB, Roy DS, Buchi M, et al. Synchronous evolution of an odor biosynthesis pathway and behavioral response. Curr Biol. 2013;7:11–20. [PMC free article] [PubMed]
32. Fischer-Tenhagen C, Tenhagen BA, Heuwieser W. Short communication: Ability of dogs to detect cows in estrus from sniffing saliva samples. J Dairy Sci. 2013;96:1081–4. [PubMed]
33. Wells DL. Dogs as a diagnostic tool for ill health in humans. Altern Ther Health Med. 2012;18:12–7. [PubMed]
34. Agostinucci W, Cardoni AA, Rosenberg P. Effect of papain on bee venom toxicity. Toxicon. 1981;19:851–5. [PubMed]
35. Ross EV, Jr, Badame AJ, Dale SE. Meat tenderizer in the acute treatment of imported fire ant stings. J Am Acad Dermatol. 1987;16:1189–92. [PubMed]
36. Baker EL, Baker WL, Cloney DJ. Resolution of a phytobezoar with Aldoph’s Meat Tenderizer. Pharmacotherapy. 2007;27:299–302. [PubMed]
37. Surico N, Codecà C, Caccia S. Medical humanities in gynecology and obstetrics. Minerva Ginecol. 2012;64:447–53. [PubMed]
38. Philippe G, Angenot L, Tits M, Frédérich M. About the toxicity of some Strychnos species and their alkaloids. Toxicon. 2004;15:405–16. [PubMed]
39. Norman G. Bisset War and hunting poisons of the New World. Part 1. Notes on the early history of curare. J Ethnopharmacol. 1992;36:1–26. [PubMed]
40. Bliss CL, Novy FG. Action of formaldehyde on enzymes and on certain pboteids. J Exp Med. 1899;1:47–80. [PMC free article] [PubMed]
41. Cao L. Immobilised enzymes: science or art? Current Opinion in Chemical Biology. 2005;9:217–26. [PubMed]
42. Pelkonen O, Abass K, Wiesner J. Thujone and thujone-containing herbal medicinal and botanical products: Toxicological assessment. Regul Toxicol Pharmacol. 2013;65:100–7. [PubMed]
43. Abass K, Reponen P, Mattila S, Pelkonen O. Metabolism of α-thujone in human hepatic preparations in vitro. Xenobiotica. 2011;41:101–11. [PubMed]
44. Holstege CP, Baylor MR, Rusyniak DE. Absinthe: return of the Green Fairy. Semin Neurol. 2002;22:89–93. [PubMed]
45. Bonkovsky HL, Cable EE, Cable JW, Donohue SE, White EC, Greene YJ, et al. Porphyrogenic properties of the terpenes camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh) Biochem Pharmacol. 1992;43:2359–68. [PubMed]
46. Jones PJ. Cleopatra’s cocktail. Class World. 2010;103:207–20. [PubMed]
47. Schmaltz F. Neurosciences and research on chemical weapons of mass destruction in Nazi Germany. J Hist Neurosci. 2006;15:186–209. [PubMed]
48. Jokanović M, Prostran M. Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr Med Chem. 2009;16:2177–88. [PubMed]
49. Kuca K, Juna D, Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini Rev Med Chem. 2006;6:269–77. [PubMed]
50. Kitada M, Kume S, Takeda-Watanabe A, Kanasaki K, Koya D. Sirtuins and renal diseases: relationship with aging and diabetic nephropathy. Clin Sci (Lond) 2013;124:153–64. [PMC free article] [PubMed]
51. Farris PK. Innovative cosmeceuticals: sirtuin activators and anti-glycation compounds. Semin Cutan Med Surg. 2011;30:163–6. [PubMed]
52. Lebeda FJ, Cer RZ, Mudunuri U, Stephens R, Singh BR, Adler M. The zinc-dependent protease activity of the botulinum neurotoxins. Toxins (Basel) 2010;2:978–97. [PMC free article] [PubMed]
53. Cartee TV, Monheit GD. An overview of botulinum toxins: past, present, and future. Clin Plast Surg. 2011;38:409–26. [PubMed]
54. Dodick DW, Diener HC, Degryse RE, Turkel CC, Lipton RB, Silberstein SD. OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand. 2014;129:61–70. [PMC free article] [PubMed]
55. Tomatsu M, Shimakage A, Shinbo M, Yamada S, Takahashi S. Novel angiotensin I-converting enzyme inhibitory peptides derived from soya milk. Food Chem. 2013;15:612–6. [PubMed]
56. Goyal N. Novel approaches for the identification of inhibitors of leishmanial dipeptidylcarboxypeptidase. Expert Opin Drug Discov. 2013;8:1127–34. [PubMed]
57. Tanaka Y, Nanamiya H, Yano K, Kakugawa K, Kawamura F, Ochi K. rRNA (rrn) operon-engineered Bacillus subtilis as a feasible test organism for antibiotic discovery. Antimicrob Agents Chemother. 2013;57:1948–51. [PMC free article] [PubMed]
58. Clardy J, Fischbach M, Currie C. The natural history of antibiotics. Curr Biol. 2009;19:437–41. [PMC free article] [PubMed]
59. Jacomella V, Corti N, Husmann M. Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease. Curr Opin Pharmacol. 2013;13:294–300. [PubMed]
60. Leung E, Hanna MY, Tehami N, Francombe J. Isolated unilateral tongue oedema: the adverse effect of angiotensin converting enzyme inhibitors. Curr Drug Saf. 2012;1:382–3. [PubMed]
61. Kujawa A, Szponar J, Szponar E, Zapalska-Pozarowska K, Kostek H. The harmfulness of drugs and slimming substances – a toxicologist’s point of view. Przegl Lek. 2012;69:548–51. [PubMed]
62. Patrono C, Rocca B. Aspirin and other COX-1 inhibitors. Handb Exp Pharmacol. 2012;210:137–64. [PubMed]
63. Aggarwal M, McKenna R. Update on carbonic anhydrase inhibitors: a patent review (2008–2011) Expert Opin Ther Pat. 2012;22:903–15. [PubMed]
64. Pavlović S, Zukić B, Stojiljković Petrović M. Molecular genetic markers as a basis for personalized medicine. J Med Biochem. 2014;33:8–21.
65. Sanders MA, Brahemi G, Nangia-Makker P, Balan V, Morelli M, Kothayer H, et al. Novel inhibitors of Rad6 Ubiquitin Conjugating Enzyme: Design, synthesis, identification and functional characterization. Mol Cancer Ther. 2013;12:373–83. [PMC free article] [PubMed]
66. Brophy JM, Costa V. Statin wars following coronary revascularization – evidence-based clinical practice? Can J Cardiol. 2006;22:54–8. [PMC free article] [PubMed]
67. Tuncay E, Seymen AA, Tanriverdi E, Yaras N, Tandogan B, Ulusu NN, et al. Gender related differential effects of Omega-3E treatment on diabetes-induced left ventricular dysfunction. Mol Cell Biochem. 2007;304:255–63. [PubMed]
68. Pekiner B, Ulusu NN, Das-Evcimen N, Sahilli M, Aktan F, Stefek M, et al. In vivo treatment with stobadine prevents lipid peroxidation, protein glycation and calcium overload but does not ameliorate Ca2+ -ATPase activity in heart and liver of streptozotocin-diabetic rats: comparison with vitamin E. Biochim Biophys Acta. 2002;9:71–8. [PubMed]
69. Ulusu NN, Ercil D, Sakar MK, Tezcan EF. Abietic acid inhibits lipoxygenase activity. Phytother Res. 2002;16:88–90. [PubMed]
70. Guz G, Demirogullari B, Ulusu NN, Dogu C, Demirtola A, Kavutcu M, et al. Stobadine protects rat kidney against ischaemia/reperfusion injury. Clin Exp Pharmacol Physiol. 2007;34:210–6. [PubMed]
71. Ulusu NN, Sahilli M, Avci A, Canbolat O, Ozansoy G, Ari N, et al. Pentose phosphate pathway, glutathione-dependent enzymes and antioxidant defense during oxidative stress in diabetic rodent brain and peripheral organs: effects of stobadine and vitamin E. Neurochem Res. 2003;28:815–23. [PubMed]
72. Tandogan B, Guvenc A, Çaliş I, Ulusu NN. In vitro effects of compounds isolated from Sideritis brevibracteata on bovine kidney cortex glutathione reductase. Acta Biochim Pol. 2011;58:471–5. [PubMed]
73. Schechter I. Mapping of the active site of proteases in the 1960s and rational design of inhibitors/drugs in the 1990s. Curr Protein Pept Sci. 2005;6:501–12. [PubMed]
74. Sohier JS, Laurent C, Chevigné A, Pardon E, Srinivasan V, Wernery U, Steyaert J, Galleni M. Allosteric inhibition of VIM metallo-lactamases by a camelid nanobody. Biochem J. 2013;15:477–86. [PubMed]
75. Ulusu NN, Tandogan B. Purification and kinetics of sheep kidney cortex glucose-6-phosphate dehydrogenase. Comp Biochem Physiol B Biochem Mol Biol. 2006;143:249–55. [PubMed]
76. Ulusu NN, Tandogan B, Tezcan FE. Kinetic properties of glucose-6-phosphate dehydrogenase from lamb kidney cortex. Biochimie. 2005;87:187–90. [PubMed]
77. Ulusu NN, Kus MS, Acan NL, Tezcan EF. A rapid method for the purification of glucose-6-phosphate dehydrogenase from bovine lens. Int J Biochem Cell Biol. 1999;31:787–96. [PubMed]
78. Ulusu NN, Tandogan B. Purification and kinetic properties of glutathione reductase from bovine liver. Mol Cell Biochem. 2007;303:45–51. [PubMed]
79. Tandogan B, Ulusu NN. Purification and kinetics of bovine kidney cortex glutathione reductase. Protein Pept Lett. 2010;17:667–74. [PubMed]
80. Bradshaw RA, Hancock CC, Krege N. 100 years of chemistry of life. 1 ed. Columbia, Maryland: 1999. p. 3.
81. Copeland RA. Enzymes-A Practical Introduction to Structure. New York: Wiley-VCH, Inc; 2000. A Brief History of Enzymology; pp. 1–11.
82. Tipton K, Boyce S. The history of enzyme nomenclature system. Bioinformatics. 2000;16:34–40. [PubMed]
83. Ben Kilani, Cö Batis H, Chastrette M. Development of the ideas concerning catalysis at the beginning of the XIXth century. Actual Chim. 2001;7–8:44–50.
84. Schadewaldt H. Nutrition and individual defense – historical considerations. Zentralbl Hyg Umweltmed. 1991;191:302–6. [PubMed]
85. Pavy FW, Siau RL. An experimental enquiry upon glycolysis in drawn blood. J Physiol. 1902;31:451–6. [PubMed]
86. Stirling W. On the Ferments or Enzymes of the Digestive Tract in Fishes. J Anat Physiol. 1884;18:426–35. [PubMed]
87. Warren G. A vital assay. Nat Rev Mol Cell Biol. 2012;13:754. [PubMed]
88. Madeira VM. Overview of mitochondrial bioenergetics. Methods Mol Biol. 2012;810:1–6. [PubMed]
89. Kohler RE. The reception of Eduard Buchner’s discovery of cell-free fermentation. 1972;5:327–53. [PubMed]
90. Henri V. General theory of the action of some glycoside hydrolases. CR Acad Sci Paris. 1902;135:919. [PubMed]
91. Harden A, Macfadyen A. Enzymes in tumour. The Lancet. 1903;162:224–5.
92. Michaelis L, Menten ML, Johnson KA, Goody RS. The original Michaelis constant: translation of the 1913 Michaelis-Menten paper. Biochem. 2011;4:8264–9. [PMC free article] [PubMed]
93. Harden A, Norris RV. The enzymes of washed zymin and dried yeast (Lebedeff). II. Reductase. Biochem J. 1914;8:100–6. [PubMed]
94. Hartridge H. An improved spectrophotometer. J Physiol. 1915;24:101–13. [PubMed]
95. Sherman HC, Thomas AW, Hinck CF. Studies on amylases. VIII. The influence of certain acids and salts upon the activity of malt amylase. JACS. 1915;37:623–43.
96. Mack E, Villars DS. Synthesis of urea with the enzyme urease. JACS. 1923;45:501–5.
97. Bastedo WA. The use and utility of digestive enzymes in therapeutics: A summary of the replies to a questionnaire submitted to the members of the American gastro-enterological association. JAMA. 1925;85:743–4.
98. Sumner JB. The isolation and crystallization of the enzyme urease: Preliminary paper. J Biol Chem. 1926;69:435– 41.
99. Madeira VM. Overview of mitochondrial bioenergetics. Methods Mol Biol. 2012;810:1–6. [PubMed]
100. Roskelley RC, Mayer N, Horwitt BN, Salter WT. Studies in cancer. VII. Enzyme deficiency in human and experimental cancer. J Clin Invest. 1943;22:743–51. [PMC free article] [PubMed]
101. Young A. Effects on plasma glucose and lactate. Adv Pharmacol. 2005;52:193–208. [PubMed]
102. Marcus M. A contribution to the history of favismo. Harefuah. 1948;15:24. [PubMed]
103. Thompson A. The c-terminal residue of lysozyme. Nature. 1952;169:495–6. [PubMed]
104. Thompson EO. The N-terminal sequence of carboxypeptidase. Biochim Biophys Acta. 1953;10:633–4. [PubMed]
105. Marks PA. A newer pathway of carbohydrate metabolism; the pentose phosphate pathway. Diabetes. 1956;5:276–83. [PubMed]
106. Koshland DE., Jr Enzyme flexibility and enzyme action. J Cell Comp Physiol. 1959;54:245–58. [PubMed]
107. Wróblewski F, Ross C, Gregory K. Isoenzymes and myocardial infarction. N Engl J Med. 1960;15:531–6. [PubMed]
108. Viswanatha T, Lawson WB, Witkop B. The action of N-bromosuccinimide on trypsinogen and its derivative. Biochimica et Biophysica Acta. 1960;40:216–24. [PubMed]
109. Smyth DG, Stein WH, Moore S. On the sequence of residues 11 to 18 in bovine pancreatic ribonuclease. J Biol Chem. 1962;237:1845–50. [PubMed]
110. Stanford RH, Jr, Marsh RE, Corey RB. Structure of lysozyme: An x-ray investigation of lysozyme chloride crystals containing complex ions of niobium and tantalum: Three-dimensional fourier plot obtained from data extending to a minimum spacing of 5. Å 1962;196:1176–8.
111. Smyth DG, Stein WH, Moore S. The Sequence of Amino Acid Residues in Bovine Pancreatic Ribonuclease: revisions and confirmations. J Biol Chem. 1963;238:227–34. [PubMed]
112. Changeux JP. Allostery and the Monod-Wyman-Changeux model after 50 years. Annu Rev Biophys. 2012;41:103–33. [PubMed]
113. Guilbault GG. Fluorometric system employing immobilized cholinesterase for assaying anticholinesterase compounds. Anal Chem. 1965;37:1675–80. [PubMed]
114. Kiefer HC, Congdon WI, Scarpa IS, Klotz IM. Catalytic accelerations of 10-fold by an enzyme-like synthetic polymer. Proc Natl Acad Sci USA. 1972;69:2155–9. [PubMed]
115. Brady RO. The lipid storage diseases: new concepts and control. Annals of Internal Medicine. 1975;82:257–61. [PubMed]
116. Kinderlerer J, Ainsworth S, Gregory RB. Computer programs for use in enzyme kinetic studies. Biochem Soc Trans. 1980;8:652–52. [PubMed]
117. Cech TR, Zaug AJ, Grabowski PJ. In vitro splicing of the ribosomal RNA precursor of Tetrahymena: involvement of a guanosine nucleotide in the excision of the intervening sequence. Cell. 1981;27:487–96. [PubMed]
118. Vadgama P. Enzyme electrodes as practical biosensors. J Med Eng Technol. 1981;5:293–8. [PubMed]
119. Pollack SJ, Jacobs JW, Schultz PG. Selective chemical catalysis by an antibody. 1986;234:1570–3. [PubMed]
120. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60. [PubMed]
121. Kay AC, Saven A, Garver P, Thurston DW, Rosenbloom BF, Beutler E. Enzyme replacement theraphy in type-I Gaucher disease. Trans Assoc Am Physicians. 1991;14:258–64. [PubMed]
122. Breaker RR, Joyce GF. A DNA enzyme that cleaves RNA. Chem Biol. 1994;1:223–9. [PubMed]
123. Changeux JP, Stuart ES. Conformational selection or induced fit? 50 years of debate resolved. F1000 Biol Rep. 2011;3:19–24. [PMC free article] [PubMed]
124. Gonzalez MJ, Miranda M, JR, Duconge J, Riordan NH, Ichim T, Quintero-Del-Rio AI, Ortiz N. The bio-energetic theory of carcinogenesis. Medical Hypotheses. 2012;79:433–9. [PubMed]
125. Weller CE, Pilkerton ME, Chatterjee C. Chemical strategies to understand the language of ubiquitin signaling. Biopolymers. 2014;101:144–55. [PubMed]
126. Kim JH, Nam DH, Park CB. Nanobiocatalytic assemblies for artificial photosynthesis. Current Opinion in Biotechnology. 2014;28:1–9. [PubMed]
127. Breithaupt H. The hunt for living gold. The search for organisms in extreme environments yields useful enzymes for industry. EMBO reports. 2001;21:968–71. [PubMed]
128. Wallerstein L. Enzymes in the fermentation industries JFI. 1917;183:531–56.
129. Blagoveschenski AV, Sossiedov MP. On the changes of wheat proteins under the action of flour and yeast enzymes. Biochem J. 1935;29:805–10. [PubMed]
130. Bommarius AS, Blum JK, Abrahamson MJ. Status of protein engineering for biocatalysts: how to design an industrially useful biocatalyst. Current Opinion in Chemical Biology. 2011;15:194–200. [PubMed]
131. Smythe CV. Microbiological production of enzymes and their industrial applications. 1951;5:126–144.
132. Demain AL, Phaff HJ. Cucumber curing, softening of cucumbers during curing. J Agr Food Chem. 1957;5:60–4.
133. Göthe CJ, Westlin A, Sundquist S. Air-borne B. subtilis enzymes in the detergent industry. Internationales Archiv für Arbeitsmedizin. 1972;29:201–8. [PubMed]
134. Shahani KM, Arnold RG, Kilara A, Dwivedi BK. Role of microbial enzymes in flavor development in foods. Biotechnol Bioeng. 1976;18:891–907.
135. Miwa T. Saccharides from starch hydrolysis and their derivatives for foodstuffs. Yuki Gosei Kagaku Kyokaishi/J Synthetic Org Chem. 1984;42:597–601.
136. Liu P, Tian GL, Ye YH. Progress in the Study on Peptide Synthesis Catalyzed by Immobilized Enzyme. Chem J Chinese U. 2001;22:1347–8.
137. Mason P. Basic concepts in clinical testing. Pharm J. 2004;272:384–6.
138. Liu XG, Ju XR, Mao XD, Zhang Z. Studies on enzymic extraction of essential oil from pine needles. Linchan Huaxue Yu Gongye/Chem Ind Forest Prod. 2005;25(3):101–114.
139. Mlichová Z, Rosenberg M. Current trends of β-galactosidase application in food technology (Review) J Food Sci Nutr. 2006;45:47–54.
140. Hsieh YHP, Ofori JA. Innovations in food technology for health. Asia Pac J of Clin Nut. 2007;16:65–73. [PubMed]
141. Selimoğlu M, Karabiber H. Celiac disease: Prevention and treatment (Review) J Clin Gastroenterol. 2010;44:4–8. [PubMed]
142. Sreedhar RP, Jhansi RD, Sulthana S. Amylases as a tool for industrial application: A review (Review) J Pure Appl Microbiol. 2011;5:167–71.
143. Galonde N, Nott K, Debuigne A, Deleu M, Jerôme C, Paquot M, et al. Use of ionic liquids for biocatalytic synthesis of sugar derivatives (Review) J Chem Technol Biot. 2012;8:451–71.
144. Hadden JA, French AD, Woods RJ. Unraveling cellulose microfibrils: A twisted tale. 2013;99:746–56. [PMC free article] [PubMed]
145. Adelakun OE, Metcalfe D, Tshabalala P, Stafford B, Oni B. The effect of pectinase enzyme on some quality attributes of a Nigerian mango juice. Nutr Food Sci. 2013;43:374–83.
146. Dettmer A, Dos APS, Gutterres M. Special review paper: Enzymes in the leather industry. J Am Leather Chem Assoc. 2013;108:146–58.
147. Li Z, Gao Y, Nakanishi H, Gao X, Cai L. Biosynthesis of rare hexoses using microorganisms and related enzymes. Beilstein J Org Chem. 2013;12:2434–45. [PMC free article] [PubMed]
148. Khawla BJ, Sameh M, Imen G, Donyes F, Dhouha G, Raoudha EG, et al. Potato peel as feedstock for bioethanol production: A comparison of acidic and enzymatic hydrolysis. Ind Crop Prod. 2014;52:144–9.
149. Tabita FR, Hanson TE, Satagopan S, Witte BH, Kreel NE. Phylogenetic and evolutionary relationships of RubisCO and the RubisCO-like proteins and the functional lessons provided by diverse molecular forms. Philos Trans R Soc Lond B Biol Sci. 2008;27:2629–40. [PMC free article] [PubMed]
150. Cavallini M, Gazzola R, Metalla M, Vaienti L. The role of hyaluronidase in the treatment of complications from hyaluronic Acid dermal fillers. Aesthet Surg J. 2013;1:1167–74. [PubMed]

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