Enzymes rather unspecific

Whereas some species oxidize host terpenes more randomly, producing an array of rather unspecific volatiles with little information, others use highly selective enzyme systems for the production of unique olfactory signals. However, apart from transformations of monoterpene hydrocarbons of host trees, oxygenated monoterpenes may well be biosynthesized de novo by the beetles (see below). 

Flavonoids, as food components or potential drugs, interact with a wide range of proteins by distinct mechanisms weak and rather unspecific binding of tannins to proline-rich or histi-dine-rich random coils leading to protein precipitation, specific enzyme inhibition, and... 

Sulfhydryl groups are reactive and very often important in the active sites of many enzymes. Some pesticides with rather unspecific action are often SH reagents. 

Metalloenzyme-catalyzed phosphoric ester hydrolysis can be illustrated by alkaline phosphatase, by far the most-investigated enzyme of this class. The protein is a dimer of 94 kDa containing two zinc(II) and one magnesium(II) ions per monomer, and catalyzes, rather unspecifically, the hydrolysis of a variety of phosphate monoesters as well as transphosphorylation reactions. The x-ray structure at 2.8 A resolution obtained on a derivative in which all the native metal ions were replaced by cadmium(II) reveals three metals in each subunit. 

Among many other peptide splitting enzymes such as (bacterial) subtilisin and thermolysin, (vegetable) papain, ficin and bromelain, (mammalian) cathepsin and others, the yeast enzyme carboxypeptidase Y finally deserves special mention. The enzyme is an exopeptidase, like carboxypeptidase A i.e. it catalyzes, rather unspecifically, the hydrolytic fission of the carboxy-terminal a-amino acids from a peptide chain. J.T. Johansen and his associates at the Carlsberg laboratory in Copenhagen showed about 10 years ago that CPD-Y is an effective catalyst of peptide bond synthesis [36]. 

In contrast to glycanases, most esterases are known to be rather unspecific enzymes. Therefore some esterases are able to act on several different hemicelluloses, as shown in Table V, whereas others are more specific and act only on one type of hemicellulose (ii). Thus, one esterase may be useful in the treatment of several different hemicelluloses. 

The polyketide synthases of micro-organisms are rather unspecific for their substrate and supplying them with a slightly different substrate from the normal can induce them to make different products. If the same is true of insect PKS enzymes, it may explain why a mixture of simple volatile alcohols and ketones of different chain length are frequently found together. For example, the mandibular glands of the ant Myrmica scabrinodis contain 3-hexanol, 3-heptanol, 3-octanol, 6-methyl-3-octanol, 3-nonanol, 3-decanol and 3-undecanol and all their corresponding ketones. 

A rather new development is the orally available renin inhibitor aliskiren. It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of hypertension. As mentioned above renin is a protease released on various stimuli from the jux-taglomerula apparatus in the kidney. Its release is the limiting step in the whole renin-angiotensin cascade. Since renin is highly substrate-specific its inhibition can be expected to have very little unspecific side effects. The result of an effective blockade of this enzyme is a reduced angiotensin I and angiotensin II formation. In contrast to ACE-inhibition or ATi-receptor blockade, the plasma concentrations of both peptides stay low. No interaction with other systems like the Kallikrenin-Bradykinin system seems to take place. 

The distribution and metabolism of protein-based biotech drugs, for example, generally follows the mechanisms of endogenous and nutritional proteins. This includes, for example, unspecific proteolysis as a major elimination pathway for proteins rather than oxidative hepatic metabolism typical for the majority of small-molecule drugs. As a consequence, drug interactions studies focused on cytochrome P-450 enzymes do not usually need to be performed for protein-based biotech drugs [17]. 

Proteolytic enzymes such as proteases and peptidases are ubiquitous throughout the body. Sites capable of extensive peptide and protein metabolism are not only limited to the liver, kidneys, and gastrointestinal tissue, but also include the blood and vascular endothelium as well as other organs and tissues. As proteases and peptidases are also located within cells, intracellular uptake is per se more an elimination rather than a distribution process [13]. While peptidases and proteases in the gastrointestinal tract and in lysosomes are relatively unspecific, soluble peptidases in the interstitial space and exopeptidases on the cell surface have a higher selectivity and determine the specific metabolism pattern of an organ. The proteolytic activity of subcutaneous tissue, for example, results in a partial loss of activity of SC compared to IV administered interferon-y. 

Since disturbed acid phosphatase activity has been associated with pathological conditions, the research has focused on the development of diagnostic methods for detection of activity as a marker for the onset of the disease, and in some extent to the development of inhibitors rather than activators to treat those conditions in which the increase in enzyme activity has a direct effect on the evolution of the disease. In particular, only the development of bisphospho-nate derivatives as inhibitors for tartrate-resistant acid phosphatase found their way to the market for treatment of osteoporosis [41], Typical inhibition of phosphatase activity includes anionic species such as L-(+)-tartrate, phosphate, vanadate, molybdate, and fluoride and neutral molecules such as formaldehyde. Vanadate ion,, is a competitive unspecific inhibitor for acid phosphatases by forming transition state analogs. Other oxoanions such as molybdate and tungstate also show inhibitory effects on... 

Fig. 4.2. Increased tyrosine concentration is caused by inborn or acquired deficiency of the first two enzymes of the tyrosine degradation pathway (the increased tyrosine concentration of tyrosinemia type I is caused by secondary deficiency of 4-hydroxyphenyl-pyruvate dioxygenase). Hypertyrosinemia in the newborn is in most instances not due to inborn errors of tyrosine metabolism, but rather to liver immaturity or other unspecific liver affections. However, whenever hypertyrosinemia is found, the pathognomonic sign of tyrosinemia type I should be excluded by a sufficiently sensitive analysis of suc-cinylacetone and related metabolites. Decreased activity of porphobilinogen synthase activity in RBC is a sensitive and easily performed marker for increased concentrations of succinylacetone, which may be used as a first line diagnostic test before positive identification of succinylacetone and related metabolites by GC-MS can be achieved. It should also be noted that increased excretion of phenolic tyrosine metabolites is always found in hypertyrosinemia and is of no differential diagnostic value...

---