Clinical Aspects

In prolonged starvation, as adipose tissue reserves are depleted there is a very considerable increase in the net rate of protein catabolism to provide amino acids not only as substrates for gluconeogenesis but also as the main metabolic fuel of the tissues. Death results when essential tissue proteins are catabolized beyond the point at which they can sustain this metabolic drain. In patients with cachexia as a result of release of cytokines in response to tumors and a number of other...

Inhibitors of Folate Metabolism Provide Cancer Chemotherapy Antibacterial Antimalarial Drugs

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymi-dylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of...

Biomedical Importance

The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not generate ATP but has two major functions (1) The formation of NADPH for synthesis of fatty acids and steroids and (2) the synthesis of ribose for nucleotide and nucleic acid formation. Glucose, fructose, and galactose are the main hexoses absorbed from the gastrointestinal tract, derived principally from dietary starch, sucrose, and lactose, respectively. Fructose and galactose are converted to...

Vitamin D Is Really A Hormone

Vitamin D is not strictly a vitamin since it can be synthesized in the skin, and under most conditions that is its major source. Only when sunlight is inadequate is a dietary source required. The main function of vitamin D is in the regulation of calcium absorption and homeostasis most of its actions are mediated by way of nuclear receptors that regulate gene expression. Deficiency leading to rickets in children and osteomalacia in adults continues to be a problem in northern latitudes, where...

Water Is An Excellent Nucleophile

Metabolic reactions often involve the attack by lone pairs of electrons on electron-rich molecules termed nucleophiles on electron-poor atoms called elec-trophiles. Nucleophiles and electrophiles do not necessarily possess a formal negative or positive charge. Water, whose two lone pairs of sp electrons bear a partial negative charge, is an excellent nucleophile. Other nucleophiles of biologic importance include the oxygen atoms of phosphates, alcohols, and carboxylic acids the sulfur of thiols...

The Regulation of eIF4E Controls the Rate of Initiation

The 4F complex is particularly important in controlling the rate of protein translation. As described above, 4F is a complex consisting of 4E, which binds to the m7G cap structure at the 5' end of the mRNA, and 4G, which serves as a scaffolding protein. In addition to binding 4E, 4G binds to eIF-3, which links the complex to the 40S ribosomal subunit. It also binds 4A and 4B, the ATPase-helicase complex that helps unwind the RNA (Figure 38-7). 4E is responsible for recognition of the mRNA cap...

Dietary Vitamin E Deficiency in Humans Is Unknown

In experimental animals, vitamin E deficiency results in resorption of fetuses and testicular atrophy. Dietary deficiency of vitamin E in humans is unknown, though patients with severe fat malabsorption, cystic fibrosis, and some forms of chronic liver disease suffer deficiency because they are unable to absorb the vitamin or transport it, exhibiting nerve and muscle membrane damage. Premature infants are born with inadequate reserves of the vitamin. Their erythrocyte membranes are abnormally...

Biochemical Research Has Impact on Nutrition Preventive Medicine

One major prerequisite for the maintenance of health is that there be optimal dietary intake of a number of chemicals the chief of these are vitamins, certain amino acids, certain fatty acids, various minerals, and water. Because much of the subject matter of both biochemistry and nutrition is concerned with the study of various aspects of these chemicals, there is a close relationship between these two sciences. Moreover, more emphasis is being placed on systematic attempts to maintain health...

Synthetic Nucleotide Analogs Are Used In Chemotherapy

Synthetic analogs of purines, pyrimidines, nucleosides, and nucleotides altered in either the heterocyclic ring or the sugar moiety have numerous applications in clinical medicine. Their toxic effects reflect either inhibition of enzymes essential for nucleic acid synthesis or their incorporation into nucleic acids with resulting disruption of base-pairing. Oncologists employ 5-fluoro- or 5-iodouracil, 3-deoxyuridine, 6-thioguanine and 6-mer-captopurine, 5- or 6-azauridine, 5- or 6-azacytidine,...

Synthesis Of Polyunsaturated Fatty Acids Involves Desaturase Elongase Enzyme Systems

Additional double bonds introduced into existing mo-nounsaturated fatty acids are always separated from each other by a methylene group (methylene interrupted) except in bacteria. Since animals have a A9 desaturase, they are able to synthesize the 0)9 (oleic acid) family of unsaturated fatty acids completely by a combination of chain elongation and desaturation (Figure 23-3). However, as indicated above, linoleic (06) or a-linolenic (o3) acids required for the synthesis of the other members of...

Short Longterm Mechanisms Regulate Lipogenesis

Adenylate Kinase Phosphorylase

Long-chain fatty acid synthesis is controlled in the short term by allosteric and covalent modification of enzymes and in the long term by changes in gene expression governing rates of synthesis of enzymes. Acetyl-CoA Carboxylase Is the Most Important Enzyme in the Regulation of Lipogenesis Acetyl-CoA carboxylase is an allosteric enzyme and is activated by citrate, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA. Citrate converts...

Ingestion Of Large Quantities Of Fructose Has Profound Metabolic Consequences

Diets high in sucrose or in high-fructose syrups used in manufactured foods and beverages lead to large amounts of fructose (and glucose) entering the hepatic portal vein. Fructose undergoes more rapid glycolysis in the liver than does glucose because it bypasses the regulatory step catalyzed by phosphofructokinase (Figure 20-5). This allows fructose to flood the pathways in the liver, leading to enhanced fatty acid synthesis, increased esterification of fatty acids, and increased VLDL...

Many Metabolic Fuels Are Interconvertible

Carbohydrate in excess of immediate requirements as fuel or for synthesis of glycogen in muscle and liver may be used for lipogenesis (Chapter 21) and hence triacyl-glycerol synthesis in both adipose tissue and liver (whence it is exported in very low density lipoprotein). The importance of lipogenesis in human beings is unclear in Western countries, dietary fat provides 35-45 of energy intake, while in less developed countries where carbohydrate may provide 60-75 of energy intake the total...

Free Fatty Acids Are Rapidly Metabolized

Generalized Lipoprotein Structure

The free fatty acids (FFA, nonesterified fatty acids, un-esterified fatty acids) arise in the plasma from lipolysis of triacylglycerol in adipose tissue or as a result of the action of lipoprotein lipase during uptake of plasma tri-acylglycerols into tissues. They are found in combination with albumin, a very effective solubilizer, in concentrations varying between 0.1 and 2.0 eq mL of plasma. Levels are low in the fully fed condition and rise to 0.7-0.8 eq mL in the starved state. In...

The Reactions Of Glycolysis Constitute The Main Pathway Of Glucose Utilization

Lipoic Acid Pathway Include Tdp

The overall equation for glycolysis from glucose to lac-tate is as follows Glucose + 2ADP + 2Pi 2l(+) - Lactate + 2ATP + 2H2O All of the enzymes of glycolysis (Figure 17-2) are found in the cytosol. Glucose enters glycolysis by phos-phorylation to glucose 6-phosphate, catalyzed by hexokinase, using ATP as the phosphate donor. Under physiologic conditions, the phosphorylation of glucose to glucose 6-phosphate can be regarded as irreversible. Hexokinase is inhibited allosterically by its product,...

Hormones Regulate Fat Mobilization

Insulin Reduces the Output of Free Fatty Acids The rate of release of free fatty acids from adipose tissue is affected by many hormones that influence either the rate of esterification or the rate of lipolysis. Insulin inhibits the release of free fatty acids from adipose tissue, which is followed by a fall in circulating plasma free fatty acids. It enhances lipogenesis and the synthesis of acylglycerol and increases the oxidation of glucose to CO2 via the pentose phosphate pathway. All of...

Analysis of Lactose Metabolism in E coli Led to the Operon Hypothesis

Jacob and Monod in 1961 described their operon model in a classic paper. Their hypothesis was to a large extent based on observations on the regulation of lactose metabolism by the intestinal bacterium E coli. The molecular mechanisms responsible for the regulation of the genes involved in the metabolism of lactose are now among the best-understood in any organism. P-Galactosidase hydrolyzes the P-galactoside lactose to galactose and glucose. The structural gene for P-galac-tosidase lacZ is...

Vitamin K Is Required For Synthesis Of Bloodclotting Proteins

Vitamin K was discovered as a result of investigations into the cause of a bleeding disorder hemorrhagic sweet clover disease of cattle, and of chickens fed on a fat-free diet. The missing factor in the diet of the chickens was vitamin K, while the cattle feed contained dicumarol, an antagonist of the vitamin. Antagonists of vitamin K are used to reduce blood coagulation in patients at risk of thrombosis the most widely used agent is warfarin. Three compounds have the biologic activity of...

Substitution of Amino Acids Causes Missense Mutations

An example of an acceptable missense mutation Figure 38-4, top in the structural gene for the P chain of hemoglobin could be detected by the presence of an elec-trophoretically altered hemoglobin in the red cells of an apparently healthy individual. Hemoglobin Hikari has been found in at least two families of Japanese people. This hemoglobin has asparagine substituted for lysine at the 61 position in the P chain. The corresponding Figure 38-4. Examples of three types of missense mutations...

Hyperbilirubinemia Causes Jaundice

When bilirubin in the blood exceeds 1 mg dL 17.1 lmol L , hyperbilirubinemia exists. Hyperbilirubine-mia may be due to the production of more bilirubin than the normal liver can excrete, or it may result from the failure of a damaged liver to excrete bilirubin produced in normal amounts. In the absence of hepatic damage, obstruction of the excretory ducts of the liver by preventing the excretion of bilirubin will also cause hyperbilirubinemia. In all these situations, bilirubin accumulates in...

The Porphyrias Are Genetic Disorders Of Heme Metabolism

The porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme they can be genetic or acquired. They are not prevalent, but it is important to consider them in certain circumstances eg, in the differential diagnosis of abdominal pain and of a variety of neuropsychiatric findings otherwise, patients will be subjected to inappropriate treatments. It has been speculated that King George III had a type of porphyria, which may account for his periodic...

Biosynthesis of Fatty Acids

Malonyl Coa Palmitate

Mayes, PhD, DSc, amp Kathleen M. Botham, PhD, DSc Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In the rat, the pathway is well represented in adipose tissue and liver, whereas in humans adipose tissue may not be an important site, and liver has only low activity. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg...

Blood Glucose Is Derived From The Diet Gluconeogenesis Glycogenolysis

Liver Glut Transporter Bidirectional

The digestible dietary carbohydrates yield glucose, galactose, and fructose that are transported via the hepatic portal vein to the liver where galactose and fructose are readily converted to glucose Chapter 20 . Metabolic amp Hormonal Mechanisms Regulate the Concentration of the Blood Glucose The maintenance of stable levels of glucose in the blood is one of the most finely regulated of all homeostatic mechanisms, involving the liver, extrahepatic tissues, and several hormones. Liver cells are...

Urea Is The Major End Product Of Nitrogen Catabolism In Humans

Synthesis of 1 mol of urea requires 3 mol of ATP plus 1 mol each of ammonium ion and of the a-amino nitrogen of aspartate. Five enzymes catalyze the numbered Figure 29-8. The glutaminase reaction proceeds essentially irreversibly in the direction of glutamate and NH4 formation. Note that the amide nitrogen, not the a-amino nitrogen, is removed. reactions of Figure 29-9. Of the six participating amino acids, -acetylglutamate functions solely as an enzyme activator. The others serve as carriers...

Polysaccharides Serve Storage Structural Functions

Polysaccharides include the following physiologically important carbohydrates. Starch is a homopolymer of glucose forming an a-glucosidic chain, called a glucosan or glucan. It is the most abundant dietary carbohydrate in cereals, pota toes, legumes, and other vegetables. The two main constituents are amylose 15-20 , which has a non-branching helical structure Figure 13-12 and amy-lopectin 80-85 , which consists of branched chains composed of 24-30 glucose residues united by 1 4 linkages in the...

Six Amino Acids Form Pyruvate

All of the carbons of glycine, serine, alanine, and cys-teine and two carbons of threonine form pyruvate and subsequently acetyl-CoA. Glycine. The glycine synthase complex of liver mitochondria splits glycine to CO2 and NH4 and forms N5,N 10-methylene tetrahydrofolate Figure 30-5 . Glycinuria results from a defect in renal tubular reabsorption. The defect in primary hyperoxaluria is the failure to catabolize glyoxylate formed by deamination of glycine. Subsequent oxidation of glyoxylate to...

Glycogenolysis Is Not The Reverse Of Glycogenesis But Is A Separate Pathway Figure 181

Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis by promoting the phosphorylytic cleavage by inorganic phosphate phosphorylysis cf hy- Glycogen 1 4 and 6 glucosyl units x Uridine disphosphate glucose UDPGlc Free glucose from debranching enzyme Free glucose from debranching enzyme To glycolysis and pentose phosphate pathway Figure 18-1. Pathway of glycogenesis and of glycogenolysis in the liver. Two high-energy phosphates are used in the incorporation of 1 mol of glucose...

Biomedically Glucose Is The Most Important Monosaccharide

Alpha Glycerose

The Structure of Glucose Can Be Represented in Three Ways The straight-chain structural formula aldohexose Figure 13 1A can account for some of the properties of glucose, but a cyclic structure is favored on thermo-dynamic grounds and accounts for the remainder of its chemical properties. For most purposes, the structural formula is represented as a simple ring in perspective as proposed by Haworth Figure 13-1B . In this representation, the molecule is viewed from the side and above the plane...

Gluconeogenesis Control of the Blood Glucose

Gluconeogenesis

Mayes, PhD, DSc, amp David A. Bender, PhD Gluconeogenesis is the term used to include all pathways responsible for converting noncarbohydrate precursors to glucose or glycogen. The major substrates are the glucogenic amino acids and lactate, glycerol, and propionate. Liver and kidney are the major gluco-neogenic tissues. Gluconeogenesis meets the needs of the body for glucose when carbohydrate is not available in sufficient amounts from the diet or from glycogen reserves. A supply of...

Allosteric Effectors Regulate Certain Enzymes

Feedback inhibition refers to inhibition of an enzyme in a biosynthetic pathway by an end product of that pathway. For example, for the biosynthesis of D from A catalyzed by enzymes Enzj through Enz3, high concentrations of D inhibit conversion of A to B. Inhibition results not from the backing up of intermediates but from the ability of D to bind to and inhibit Enzj. Typically, D binds at an allosteric site spatially distinct from the catalytic site of the target enzyme. Feedback inhibitors...