1. Indeed, cyanobacteria are the prokaryotic precursors of chloroplasts, the photosynthetic organelles of plants. Like mitochondria, chloroplasts are endosymbionts of prokaryotic origin and still retain their own genomes and ribosomes. ↗
  2. Carnivorous plants could be considered both autotrophs and heterotrophs. It seems, however, that plants evolved this lifestyle mostly to secure a supply of organic nitrogen rather than of carbon. ↗
  3. Until the early 20th century, the only practical source of nitrogen fertilizer was guano, which is accumulated, dried bird poop. It is found in large deposits on cliffs and islands off the South American west coast, and clippers ferrying the precious stuff used to go back and forth between Chile or Peru and Europe or North America.
    In 1909, Haber and Bosch devised a synthetic method for producing nitrogen fertilizer, as well as nitrogen-based explosives. In this process, the reaction N2+3H22NH3 is induced by brute force: a mixture of the two gases is compressed to very high pressures and heated to high temperature in the presence of a metal catalyst. The method has been in use ever since for producing nitrogen fertilizer. Among all the great inventions that have propelled the growth of the world population, the Haber-Bosch process likely is the single most important one. ↗
  4. The bile duct and the pancreatic duct join the duodenum, that is, the uppermost part of the small intestine, at the same site (termed the papilla duodeni major). Bile stones traveling down the bile duct may get stuck at this orifice and obstruct both secretory ducts. On top of bile colics, this may then result in acute pancreatitis, in which the backed-up pancreatic enzymes start digesting the pancreas itself. This is both exceedingly painful and a major, acutely life-threatening calamity. ↗
  5. Extracellular digestion is employed by most organisms. Even bacteria secrete digestive enzymes and take up substrates only at the stage of the monomeric breakdown products. Why is that so? ↗
  6. If you already have some lab experience, you may have treated cells with trypsin or fragmented DNA with pancreatic DNAse, and may remember that these enzymes work best at pH 7.5–8. ↗
  7. An exocrine gland secretes outwardly; this definition includes secretions into the digestive tract. An endocrine gland secretes into the bloodstream. The products of endocrine glands are invariably hormones. ↗
  8. Bile acids solubilize fat (triacylglycerol) effectively because they are detergents with a high critical micellar concentration (see slide 10.2.2). For the same reason, they are also useful for removing tough stains from your laundry. ↗
  9. The party trick that prevents bacterial colonization of our other hollow organs is to discharge and replace the fluids more rapidly than the bacteria can grow. Accumulation and stasis of fluid invariably leads to bacterial overgrowth and often infection; examples are recurrent urinary tract infections when bladder function is impaired, and the respiratory infections facilitated by viscous, slowly flowing bronchial secretions in patients with cystic fibrosis. ↗
  10. This commendable enzyme, residing in the liver, degrades ethanol, and without it, some of us might be drunk all the time! ↗
  11. Striated muscle comprises skeletal muscle and heart muscle. The second major type of muscle tissue is smooth muscle, which occurs in blood vessels and internal organs and is under control by the autonomic nervous system. ↗
  12. Aldolase is sometimes referred to as aldolase A, in order to distinguish it from aldolase B, which occurs in fructose degradation (see slide 4.2.1) ↗
  13. Measurement of the blood lactate concentration is performed in sports medicine to gauge the capacity of a trained athlete to sustain aerobic rather than anaerobic metabolism during prolonged exertion. The anatomical correlate of endurance is not so much the quantity of muscle tissue but the extent of its vascularization, that is, the abundance of capillaries in the tissue. A high density of capillaries ensures good oxygen supply. ↗
  14. The English name of this organism is baker’s yeast, but the literal translation of the scientific name would be “sugar fungus of the beer”. ↗
  15. Glucokinase also binds glucose cooperatively, as is evident from the slightly sigmoidal shape of the graph. Interestingly, glucokinase is a monomer; apart from the active site, it also has a regulatory, allosteric glucose binding site [4].
    More detailed analysis shows that there are more than two variants of glucose-6-kinase activity, and that organs may express more than one variant. ↗
  16. Haima is the Greek word for blood; haematology or hematology is the medical discipline that deals with diseases of the blood. ↗
  17. Galactose is contained in the glycosyl moieties of many glycoproteins and glycolipids. The enzymes and activated intermediates for the synthesis of galactose from glucose and for its incorporation into glycosyl moieties are widespread among life forms. They predate the emergence of lactose secretion by mammals, and evolution chose to reuse them for lactose utilization. ↗
  18. Alternatively, we might say that pyruvate is exchanged for an OH ion; the net effect is virtually the same. ↗
  19. You will notice that the name “pyruvate dehydrogenase” is ambiguous, denoting both the entire complex and the first subunit. ↗
  20. The pyruvate dehydrogenase complex remains intact when purified from cell extracts. With some other enzymes, there is evidence that they form functional complexes in vivo, even though they are recovered after cell disruption and protein purification procedures as individual and functional molecules. For example, malate dehydrogenase and citrate synthase may associate in vivo, so that oxaloacetate may pass directly from one to the other [14]. Another intriguing example is the association of glycolytic enzymes with the outer surface of the mitochondria [15]. ↗
  21. Yes, strictly speaking, coenzyme A is a cosubstrate, since it is transformed from one state to another in the reaction; a true coenzyme should emerge from the reaction unchanged, just like the enzyme. As you can see, the distinction between coenzymes and cosubstrates is not strictly maintained in the traditional nomenclature. ↗
  22. Note that only the thiazole ring of TPP is shown in this slide; its second ring is represented by R1. ↗
  23. The same applies also to e.g. glycogen synthase and phosphorylase (see section 8.4). ↗
  24. Karin Borges pointed out to me that there seems to be no published evidence of PDH activation by fructose-1,6-bisphosphate with the mammalian enzyme; all the evidence I could find pertains to the E. coli enzyme [16,17]. Considering that in eukaryotic cells glycolysis and PDH reside in distinct compartments, fructose-1,6-bisphosphate is indeed unlikely to regulate PDH in mammals. ↗
  25. Where exactly do the two water molecules enter the TCA cycle? For one of them, it is obvious (see step 7 in slide 5.4.3). However, the second one is a bit harder to spot. Hint: it is not the H2O that hydrolyzes off the acetyl-CoA in the citrate synthase reaction, since that is already accounted for by substituting acetate for acetyl-CoA in our simplified reaction scheme. ↗
  26. If we consider the standard enthalpies of formation of water, acetate, and carbon dioxide, it turns out that the reaction, as written, has a ΔH of approximately 300 kJ/mol. This energy is offset by the hydrolysis of coenzyme A and by binding the abstracted hydrogen to NAD+ and FAD (see below). ↗
  27. As mentioned before, the porins in the outer mitochondrial membrane are permeable for most small molecules and ions, and thus the proton concentration in the space between the two mitochondrial membranes equilibrates readily with the cytosol. The proton concentration gradient that powers ATP synthesis therefore exists across the inner mitochondrial membrane only. ↗
  28. The cytochromes of the abundant mitochondria give this tissue its brown color; the white color of regular fat tissue tells us that its density of mitochondria must be low. ↗
  29. Dinitrophenol is a hydrophobic molecule, and it therefore is not surprising that it can cross membranes in protonated form. However, the high membrane permeability of its deprotonated, negatively charged form is unusual. This is related to the two electron-withdrawing nitro groups, which cause the negative charge to be highly delocalized; this prevents the molecule from attracting a tightly bound hydration shell that otherwise would interfere with its permeation across the membrane. ↗
  30. Drawn from 3m9s.pdb, 2fbw.pdb, 3cx5.pdb, 2zxw.pdb, and 3cyt.pdb, after a figure in [19]. ↗
  31. In contrast to complexes I, III and IV, complex II does not span the entire membrane; this readily suggests that proton translocation will not occur here. ↗
  32. Electrons do occur free as β particles in ionizing β radiation. However, to escape capture by molecules, β particles must possess an amount of energy much higher than those available in biochemical or other chemical reactions. When β particles impinge on a solid body, they dissipate their energy by breaking up any molecules in their path into radicals or ions, until they are finally captured again. ↗
  33. Some of the hemes in the respiratory chain are referred to as “cytochromes.” Somewhat confusingly, the same term is, with other molecules, applied to the entire complex of a heme and the protein it is bound to. ↗
  34. Electron buffering between NADPH and heme by flavins occurs in cytochrome P450 reductase (see slide 19.2) and in nitric oxide synthase (slide 9.3.5). ↗
  35. In addition to its role in the respiratory chain, cytochrome C is also an important intracellular signaling molecule; its release from damaged mitochondria triggers apoptosis (programmed cell death; see reference [20] and slide 19.5.1). Another molecule with surprising connections to apoptosis is glyceraldehyde-3-phosphate dehydrogenase [21]; this enzyme is reportedly associated with the outer mitochondrial membrane. ↗
  36. Remember that the volt, which is the unit of ΔE, is defined as joule/coulomb, since voltage = energy/charge, hence the need for Faraday’s constant.
    Like Avogadro’s number, Faraday’s constant is a relic of history, required only because the physical units of mass and electrical charge had already been arbitrarily chosen before the inherent masses and charges of atoms and electrons were discovered. One could in principle define a system of units without either of these crummy numbers. Indeed, chemists often give masses in Daltons, and physicists give energies in electron volts (eV), in order to avoid them.
    The minus sign in equation 6.1 results from the fact that the electron-donating electrode, the cathode, is considered negative. This is entirely arbitrary and meaningless, but it is also very handy as a trap in exam questions. ↗
  37. You have encountered the same concept with chemical elements as their electronegativity: An element with a high electronegativity holds on to electrons particularly tightly, i.e. it has a high affinity for electrons. ↗
  38. Note that this number is at variance with the mechanism of the coenzyme Q cycle given above, which ejects four protons for each equivalent of ubiquinone. Different sources offer varying numbers. ↗
  39. Above a potential of 150 mV, the inner membrane becomes increasingly leaky for protons (see section 6.10), so that such higher potentials will not be sustained. ↗
  40. A similar molecular motor drives the rotation of the flagella found in many bacteria, which enables them to swim. Remember that mitochondria are of bacterial origin. ↗
  41. The periplasmic space is the the narrow space between the inner and the outer mitochondrial membrane. ↗
  42. A steam engine gets around a similar problem by employing inertia, which is provided by a nice, heavy, cast-iron flywheel. That is not possible here because of the minuscule dimensions. A student who took my class in 2005, Kelvin Cheung, took on the challenge to calculate the kinetic energy of rotating ATP synthase; it works out to about one billionth of the energy required for making 1 ATP. ↗
  43. This futile cycle might also contribute significantly to the proton leak that occurs at high levels of the proton-motive force (see section 6.10 above). ↗
  44. Glycogenin is a dimer, which causes two molecules of glycogen to be associated non-covalently with each other also. ↗
  45. Cooking starch has the effect of breaking up hydrogen bonds within amylose and increase its degree of hydration. Amylose thereby becomes digestible by amylase. Cooking food ranks among mankind’s greatest inventions, almost comparable to Twitter and the iPad. ↗
  46. Undegraded insoluble glycogen particles may be seen inside the cells of aged individuals. Such particles are described as corpora amylacea (‘starchy bodies’) in the brain and as cardiac colloid in heart muscle. ↗
  47. Wherever pyrophosphate is released, it is subsequently cleaved to two phosphate ions by pyrophosphatase. This cleavage is strongly exergonic and keeps the concentration of pyrophosphate very low, which in turn makes its release more exergonic. The release of pyrophosphate therefore provides a stronger push to a reaction than the release of monophosphate. ↗
  48. Phosphorolysis also occurs in the release of ribose and deoxyribose from nucleosides (see section 16.4). ↗
  49. Glycogen arose early in evolution, and the glycogen usage pattern of early organisms likely resembled muscle rather than liver tissue. Therefore, the energy efficiency of phosphorolysis was advantageous to those early organisms, too. ↗
  50. This mechanism bears some resemblance to the hyperuricemia that can be triggered in healthy patients through fructose overload (see slide 16.6.4). ↗
  51. Maltose is a suitable model substrate, but the real role of this “maltase” enzyme is to cleave the α(1→4)-glycosidic bonds in glycogen. ↗
  52. The two enzymes do share a common subunit, which may occasionally may be deficient also [42]. ↗
  53. If we use the same concentrations of reduced and oxidized forms in vitro, the difference in their redox potentials is very small; that is, both have virtually the same standard redox potentials. ↗
  54. The exchange of isocitrate for malate is electroneutral, and thus does not derive additional drive from the proton-motive force. ↗
  55. Antimalarial drugs such as quinine and chloroquine inhibit hemozoin accretion and thereby expose the parasites to the toxic effects of free heme; this is understood to be their major mechanism of action. ↗
  56. Unsaturated fatty acids are classified according to the distance of the double bonds from the far (ω) end; for example, linoleic acid is an ω6-fatty acid, since the first double bond occurs after the 6th carbon from the ω end. Linolenic acid has an additional double bond after the third carbon and is therefore a ω3-fatty acid. Neither ω3 and ω6 fatty acids can be synthesized in human metabolism; they are therefore essential, i.e. strictly required components of our diet. In contrast, the ω9 fatty acid oleate can be produced in human metabolism (see slide 10.5.8). ↗
  57. Curd soap is prepared simply by alkaline hydrolysis of fat; it consists of the sodium salts of the fatty acids released. ↗
  58. It is this property that makes them useful in treating laundry also. ↗
  59. Considering that the resynthesis immediately after cleavage is energetically costly, one might wonder why these two steps are necessary; it might seem more economical to absorb fat molecules without cleavage. My own tentative interpretation is that the complete dispersal and degradation of triglycerides serves as a security screen. If droplets of ingested fat were allowed to enter the system wholesale, a lot of fat-soluble, potentially toxic compounds dissolved in them could sneak into the system unchecked. ↗
  60. This slow but steady flow of fluid through all tissues is also important for immune surveillance: when a lymph vessel traverses a lymph node, the resident macrophages and lymphocytes sample the lymph fluid for unusual antigens that would signal an infection upstream, and will promptly mount an immune response to such antigens. ↗
  61. At this point, we might again wonder why the transport of fat from the intestines to other tissues is so complicated—it might seem easier to do just pour the free fatty acids into the bloodstream. One reason is that free fatty acids are toxic. As mentioned before, they are detergents—and detergents dissolve cell membranes. (Interestingly, the membranes of the intestinal cells withstand very high concentrations of bile and fatty acids! They manage this due to their high content of ceramide, which is also found in the keratin of the skin.) However, as we will see later, fatty acids with shorter acyl chains are indeed transported in free form. ↗
  62. This also holds in other pathways and for CHNH bonds. The only exception I’m aware of is the dehydrogenation of glycerophosphate in the glycerophosphate shuttle. ↗
  63. The word carnis is Latin for meat—as in chili con carne. ↗
  64. A second pathway from acetol to pyruvate involves the oxidation of acetol by cytochrome P450 2E1 to methylglyoxal, which is then converted to d-lactate through addition and subsequent hydrolysis of glutathione [56]. ↗
  65. Considering the very high concentrations of ketone bodies in diabetic coma, one might assume that acetone contributes to the causation of unconsciousness in this condition. However, a clinical study on this question has concluded that acetone is likely not a dominant factor [58]. ↗
  66. In E. coli, the phosphopantetheine group is associated with a separate small protein, the acyl carrier protein (ACP). In mammalian fatty acyl synthesis, ACP is not a separate protein but is part of the synthase molecule itself. ↗
  67. I look forward to the discoveries of metabolic derailments these drugs will cause in the face of continued excess caloric intake. What is going to become of the surplus acetyl-CoA when fatty acid synthesis is inhibited: Ketone bodies? Cholesterol? Will glycolysis be backed up and diabetes be induced? All of the above? ↗
  68. The molecule shown as the product of reaction 4 is indeed an intermediate of the diphosphomevalonate decarboxylase reaction; the enzyme itself transiently attaches the third phosphate which it then immediately employs as a leaving group. ↗
  69. INSIG stands for “insulin-induced gene.” ↗
  70. The name of “abetalipoproteinemia” denotes the lack of apolipoprotein B, which is the major protein constituent of both chylomicrons and VLDL. ↗
  71. LDL manages to leave the circulation by transcytosis, that is, endocytosis by the vascular endothelial cells on the luminal side, followed by exocytosis on the opposite side. ↗
  72. The German vernacular name for this condition translates as “window shopping disease”—not uncommonly, afflicted patients stop before every window display, feigning interest, in order to disguise their predicament. ↗
  73. The appearance of empty “bubbles” inside the foam cells is an effect of the tissue fixation and staining technique: Organic solvents used in fixation wash out lipids, and most histological dyes bind to proteins or nucleic acids but not lipids. ↗
  74. Of note, Adams died at 49, only a few years after finishing his book “The Hitchhiker’s Guide to the Galaxy,” in which he exposed the far-ranging conspiracy of mice. It would seem that the mice exacted their revenge! ↗
  75. These essential amino acids are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Arginine can be synthesized but apparently not always in sufficient amounts, and thus is often listed as the tenth essential amino acid. ↗
  76. Since we already know how to degrade pyruvate, transamination is all that is required to account for the degradation of alanine. Similarly, as we had seen in slide 6.9.2, aspartate is transaminated to oxaloacetate, which again suffices to account for its utilization. ↗
  77. At the outset, PLP actually forms a Schiff base with a lysine side chain of the enzyme, which is then displaced by the incoming substrate; these steps have been skipped here for simplicity. The liberated lysine then assumes the role of the catalytic base, which is represented here by B. ↗
  78. While this bit of nomenclature may be surprising in its nonchalance, we should probably be grateful that it did not fall to some Old World biochemists with classical inclinations to dream up a name for the behavior. The mind boggles at the possibilities—perhaps: Antidromo-binary vacillatory allochronic? ↗
  79. In liver cirrhosis, one of the main problems is the lacking capability of the liver to detoxify ammonia derived from bacterial metabolism in the large intestine. Oral antibiotics (e.g. paromomycin) are used in this condition to reduce bacterial growth and ammonia formation.
    Some ammonia is excreted with the urine as well, where it serves to buffer surplus protons also destined for excretion. However, this ammonia is not extracted from the circulation but is formed from glutamine directly in the kidneys. ↗
  80. Some cell types, including leukocytes and the intestinal epithelia, use glutamine rather than glucose as their major energy-providing substrate. ↗
  81. The reaction mechanism of glutamine synthetase is shown in slide 2.4.1. ↗
  82. The enzyme used for this treatment is purified from E. coli. In healthy patients, repeated injections of a bacterial protein would soon induce antibodies, which would quickly render the enzyme inactive. However, in leukemia patients, the disease itself, and the cytotoxic drugs simultaneously applied—such as, for example, cytosine arabinoside (slide 16.9.7)—conspire to suppress antibody formation. If it occurs anyway, enzyme prepared from another bacterium, Erwinia chrysanthemi, can be used. The immunogenicity of the bacterial enzymes can be reduced by derivatization of the protein with polyethyleneglycol (PEG). ↗
  83. The relay of electron density effects by conjugated C=C double bonds is referred to as the vinylogous effect. ↗
  84. As you may have guessed, that full name was a straight copy-and-paste job. ↗
  85. In modern practice, one could likely prevent this using protease inhibitor cocktails; however, such inhibitors were not available at the time. ↗
  86. More recently, recombinant insulins with point mutations have been introduced into clinical treatment. Interestingly, these insulins seem to be less prone to antibody induction than porcine and bovine insulins were. This may be due to their reduced tendency to form aggregates (see slide 14.5.11). ↗
  87. The rate of GTP cleavage is modulated by special regulatory proteins, which we will not go into here. There just seems to be no end to the layers, convolutions and intricacies of signal transduction in cells; compared to it, metabolism is positively sane, simple and elegant. ↗
  88. Diabetes insipidus is due to the lack of anti-diuretic hormone (ADH), a peptide secreted from the posterior hypophyseal gland. This hormone promotes the retention of water by reuptake in the collecting duct section of the nephron (see below). Loss of ADH production, typically due to a lesion of the hypophyseal gland, results in a dilute urine, but without loss of glucose or other metabolites. ↗
  89. Osmotic diuresis can also be induced with other solutes. The sugar alcohol mannitol has been used in this manner to speed up the elimination of drugs and poisons, but this treatment appears to be no longer in common use. ↗
  90. Indeed, protein degradation is activated beyond the muscle’s own metabolic needs by signaling pathways that also cause muscle wasting in chronic inflammation and cancer [89]. ↗
  91. Other possible forms of acidosis are accumulation of lactate (lactic acidosis) and respiratory acidosis, which is due to insufficient removal of CO2 through the lungs. Lactic acidosis can be induced by oral metformin and related oral antidiabetic drugs (see slide 14.5.14). ↗
  92. The abbreviation HLA stands for human leukocyte antigen, but HLA molecules are found on all nucleated cells, not just leukocytes. They are, however, not found on red blood cells, which have no protein synthesis and thus no use for HLA molecules. HLA molecules are very diverse between individuals; this is what makes them antigens. Their absence on red blood cells explains why blood transfusions are far less fraught with immunological incompatibilities than are organ transplants. ↗
  93. A similar mechanism also produces the clonal variation of antibody specificities in B lymphocytes. ↗
  94. Failure of the T suppressor cells to eradicate autoreactive T helper or T killer cells will result in autoimmune diseases. ↗
  95. The diversity of HLA antigens among humans is believed to have arisen through the exposure to different infective agents that selected for different HLA antigens. Association of specific HLA alleles with protection from infection is documented for various pathogens, including HIV [92]. ↗
  96. This scenario was of some practical significance in the past, but is largely hypothetical now that glucose meters have become ubiquitous. However, it still serves to illustrate the danger of hypoglycemia. ↗
  97. The number of stacked bilayers surrounding the axon in this picture is approximately 20, but it can be substantially higher in the fastest-conducting axons. ↗
  98. Some theoretical principles seem to be forever stuck with the byword “hypothesis,” such as the current one or the “Mary Lyon hypothesis” (see slide 9.4). Both hypotheses are actually well supported by observation; see [109] for experimental evidence supporting the methyl trap hypothesis. ↗
  99. The acyl carrier protein (ACP) domain that is found in fatty acid synthase is basically coenzyme A with adenosine replaced by a peptide moiety (see slide 10.5.3). This is possible since ACP is the private property of fatty acid synthase and does not need to function with other enzymes.
    The constraining effect of a large number of interactions can also be seen with peptides like glutathione or proteins like calmodulin, which are also very strongly conserved throughout evolution. ↗
  100. Unlike regular alanine, β-alanine carries the amino group on the second carbon from the carboxyl group. This position is also referred to as the β carbon, whereas the first one is the α carbon. ↗
  101. You may recall that base-specific chain termination by dideoxy-nucleotides is the basis of the Sanger method of DNA sequencing. If you don’t, consider yourself reprehended. ↗
  102. Methemoglobin reductase also participates in reductive metabolism of drugs and xenobiotics (see section 19.4). In that context, it is often referred to as diaphorase.
    Interestingly, methemoglobin binds cyanide ions more avidly than reduced hemoglobin does. This is used in the treatment cyanide poisoning: Controlled application of oxidizing agents—such as dimethylaminophenol or sodium nitrite, [132]—turns some hemoglobin into methemoglobin, which then captures cyanide and prevents its binding to hemes in the respiratory chain. It seems, however, that treatment with hydroxycobalamin is superior (see section 15.5.5) ↗
  103. Generally speaking, any kind of psychiatric disturbance can potentially be due to organic causes, and therefore a thorough medical history and examination is necessary in each psychiatric patient. If you decide to become a psychiatrist, make it a point not to forget about your neurology and internal medicine. ↗
  104. Prior to birth, the bilirubin formed by the fetus is eliminated via the placenta and therefore does not accumulate. The same applies to the toxic metabolites that accumulate in phenylketonuria (see slide 12.5.1) and several other hereditary metabolic diseases, which therefore become manifest only after birth. ↗
  105. And in case you’re not convinced yet—don’t forget that you want to pass your exam! ↗
  106. Chromatin compaction—the tight packing of parts of the genome not currently in use by a given cell—serves to protect the DNA from radiation damage [145]. This DNA can still be damaged by radiation, but in this case direct effects of e.g. Compton scattering on the DNA may be more important than water-soluble reactive species [146]. ↗
  107. One exception to this rule is neutron radiation, which acts mostly by knocking free protons; each of these, in turn, will knock free multiple electrons. ↗
  108. In diffusion, time is proportional to distance squared; therefore, the differences in lifetime are even more pronounced than visually apparent. Moreover, this figure even exaggerates the diffusion distance of OH—according to [148], OH on average traverses only five times its own molecular diameter. Such a short distance fits with its use for the molecular foot-printing of DNA. ↗
  109. Most of the species shown are indeed radicals, but the solvated free electron and iron (Fe++/Fe+++) are obviously exceptions. ↗
  110. Other interesting molecules in this antimicrobial cocktail are peptidases (cathepsins) and cationic antimicrobial peptides (defensins). ↗
  111. As noted above, NADPH oxidase is also expressed by other cell types, for the sake of signaling; the activities found in those cells are far lower than in phagocytes. ↗
  112. At neutral or higher pH, O2•− remains unprotonated, and the mutual electrostatic repulsion between O2•− anions inhibits their reaction. Under these conditions, superoxide dismutase is required to bring about the disproportionation of 2 O2•− anions to H2O2 and O2. ↗
  113. The condition is known as chronic granulomatous disease—infectious foci that in healthy patients would resolve quickly turn into persistent and hardened granulomas, in which macrophages encircle the pathogens and fight a protracted battle against them. ↗
  114. Examples are pleura mesothelioma in asbestosis and hepatocellular carcinoma in chronic virus hepatitis. ↗
  115. Amazingly, as neutrophil granulocytes sacrifice themselves, they spill their DNA and turn it into a device for trapping extracellular pathogens, the so-called neutrophil extracellular traps, or NETs for short [155]. ↗
  116. Since thyroid hormones transcriptionally induce uncoupling proteins, one might expect that they would also interfere with insulin secretion. This could contribute to the secondary diabetes observed in hyperthyroidism. However, I have not found corroborating evidence for such a mechanism in the literature. ↗
  117. In addition to the dosage, the type of radiation also affects the biological effect. γ-Radiation is penetrating; it thus does not lose much energy along its path through the tissue (technically: it has a low rate of linear energy transfer), and the OH radicals generated by one γ-particle are spread relatively thin. Other types of ionizing radiation such a α, β, or fast neutrons don’t penetrate quite as deep. They thus deposit their energy along a much shorter path and generate OH radicals at higher local concentrations. Particularly with α-radiation and neutrons, this results in higher rates of double-strand breaks, which means that, at equal energy dosages, these types of radiation are more harmful than γ-rays. Weighting factors are used to account for this difference in biological effectiveness; the product of an energy dosage expressed in Gray (Joule/kg; Gy) and the appropriate dimension-less weighting factor for the type of particle in question is given the unit Sievert (Sv). ↗
  118. Similar reactions also occur in regular pathways. N-formylkynurenine is an intermediate in tryptophan degradation. Dimerization of tyrosine side chains, subsequent to their oxidative iodination, also occurs in the synthesis of thyroid hormones by thyroid peroxidase, which generates H2O2 as a reaction intermediate. ↗
  119. The term bisallylic signifies that such methylene groups form an allyl group with each of the adjacent double bonds. ↗
  120. This subject is treated in more detail in my Biochemical Pharmacology lecture notes. ↗
  121. This is the structure of a lipoxygenase from soybean (1ik3.pdb); however, human lipoxygenases are very similar in structure and mechanism. ↗
  122. Tumor cells have been observed to form and/or retain porphyrins at higher concentrations than do regular, non-tumorous cells. With tumors of hollow organs such as bladder and bronchi, this may be used for photodynamic therapy—a light source is introduced using an endoscope, and light is shone onto the porphyrin-enriched tumors in order to destroy them [180]. ↗
  123. This study used CuSO4, which contains Cu++, not Cu+, and the authors ascribe the observed lipid peroxidation to Cu++. However, I don’t see how Cu++ would do the trick. Interestingly, the study did show that Fe++, but not Fe+++ could substitute for copper. Therefore, I assume that some reducing agent was present that converted Cu++ to Cu+, and I have taken the liberty of drawing the latter as the active principle. ↗
  124. Accumulation of free heme also constitutes a problem for malaria parasites, and some antimalarial drugs act by interfering with the parasite’s mechanisms of heme sequestration (see section 9.4.3). ↗
  125. As discussed in chapter 17, the major intracellular storage form of iron is ferritin. While ferritin iron is normally in the Fe+++ form and fairly inert, it can be reduced to Fe++ and thereby released by some strong reducing agents, including the reduced forms of the pyrimidines found in Vicia faba [184]. Since ferritin is also found in erythrocytes [185], this likely contributes to the lipid peroxidation and membrane disruption in favism (see section 9.4.1). ↗
  126. Protein-disulfide isomerase can apparently also reduce dehydroascorbate. Overall, it appears that pathways for reductive regeneration of radical scavengers are quite promiscuous, and this may account for the similarly promiscuous reductive metabolism of drugs. ↗
  127. Intriguingly, when the primates split from other mammals, they lost the pathways both for ascorbate synthesis and for urate degradation to allantoin. It has been suggested that the use of urate as the preferred antioxidant is important for primate, and particularly human, longevity. While some statistics presented in support are intriguing [194], I have not found a clearcut biochemical rationale for such an effect. ↗
  128. Vitamin E is a mixture of different tocopherol and tocotrienol variants and stereoisomers. While all of these may inhibit lipid peroxidation in vitro, one specific isomer—RRR-α-tocopherol—is the most important one in human metabolism, since it is preferentially taken up and transported. ↗
  129. Since selenocysteine is translationally encoded by a stop (UGA) codon, translation may terminate prematurely whenever such a codon is encountered; this gives rise to a number of truncated variants of with selenoprotein P. Some of these are small enough to be lost by filtration in the kidneys; it is interesting to note that a reuptake mechanism exists for recovering such fragments, and the selenium they contain. ↗
  130. It has been proposed, however, that the cyclical reduction of ubiquinone is linked to proton pumping not just in the respiratory chain, but also in lysosomal membranes [197]. In this context, it matters that UQH does not stay together (as drawn here for simplicity) but sheds its proton into solution. While the proposed proton transport mechanism seems plausible to me, the concomitant generation of OH reported in the study cited was likely due to the lack of O2•− scavengers in the experiment. ↗
  131. In the molecular structures, there also are some discontinuities. These represent conformationally flexible segments of the polypeptide chain that did not give rise to distinct diffraction signals. ↗
  132. If you are wondering now how this can be done without suppressing the orderly termination of translation at the regular stop codon, I have no answer for you, but nevertheless commend you for paying attention. In case you were not wondering about this, you were probably not really studying but just cramming for the exam.
    Translational miscoding will not usually restore the original amino acid that was present before the stop mutation occurred. Therefore, a further requirement is that the amino acid residue in question is not critical for protein activity. ↗
  133. An identical twin would not be helpful with ADA deficiency, because he or she would suffer from the same enzyme defect. However, identical twins come in handy with bone marrow transplants in leukemia; the same goes for other organ transplants. Therefore, I urge you to get yourself a twin at the earliest opportunity. ↗
  134. One might expect priapism to occur in hemolytic crises in glucose-6-phosphate dehydrogenase deficiency also; anecdotal evidence seems to support this assumption [213]). Furthermore, one might consider the therapeutic potential of adenosine receptor agonists in erectile dysfunction [214]. ↗
  135. A good review on the use of PEG to modify enzymes and other therapeutic proteins is [217]. ↗
  136. Myeloablative conditioning is the norm in allogenic bone marrow transplants, which is most commonly performed as the treatment of last resort in leukemia or lymphoma patients. ↗
  137. In case you are wondering about the very high Newton values in the graph—they are the sums of the strength measurements on several separate muscle groups. ↗
  138. Another question is how the enzyme, which is injected intravenously, manages to the leave the circulation and reach the extracellular space in muscle tissue. It seems possible to me that the mannose-6-phosphate receptor also facilitates transcytosis through the capillary endothelium. ↗
  139. Another aspect that likely facilitates the uptake of enzyme by macrophages is the absence of an endothelial barrier. While muscle cells are separated from the blood flow by a continuous endothelium, the macrophages in the spleen and liver reside directly within the blood-percolated sinusoids. ↗