Lipoproteins and Cardiovascular Diseases
ONE-CARBON METABOLISM
5. Choline can donate 3 hydroxymethyl groups.
Interconversion of One-carbon Groups
The different one-carbon groups are interconvertible as shown in Figure 12.20. All one-carbon units are ultimately siphoned into methyl-THFA.
From methyl-THFA, the B12 co-enzyme accepts the methyl group to form methyl cobalamin. It then transfers the methyl group to homocysteine to form methionine (Fig. 12.20).
Utilization of One-carbon Groups
The one-carbon units are used for synthesis of the following compounds (Fig. 12.20):
i. Carbon atoms 2 and 8 of purine ii. Glycine synthesis (Fig. 12.7) iii. Serine synthesis
iv. Choline synthesis
v. Tra nsme thylation rea ctions including creatine, choline and epinephrine synthesis (Table 12.2).
Inborn Errors of Metabolism
Sir Archibald Garrod in 1902 reported four diseases, now known as Garrod's tetrad. These are alkaptonuria, albinism, pentosuria and cystinuria. Garrod introduced the term "inborn errors of metabolism" in 1908.
Inborn errors associated with protein metabolism: • Phenyl ketonuria (Fig. 12.15)
• Alkaptonuria (Fig. 12.15) • Albinism (Fig. 12.15)
• Homocystinuria (Table 12.3) • Urea cycle defects (Table 12.1).
Inborn errors associated with carbohydrate metabolism are:
• Glycogen storage diseases (see Table 5.7) • Glucose-6-P-dehydrogenase deficiency (see
Fig.7.1)
Table 12.5: Summary of amino acid metabolism
Amino acid Compound formed Reaction Function
Glycine Heme Condenses with succinyl CoA Oxygen carrying part of
hemoproteins
Do Creatine Reacts with arginine to form Creatine phosphate is
guanidoacetic acid which is then high energy compound methylated to form creatine in muscle
Do Glutathione Gamma glutamylcysteinyl glycine Antioxidant in RBCs
Do Purine bases C4,C5 and N7 of purine ring is Purine nucleotides in
contributed by glycine DNA and RNA
Do One carbon group Glycine cleavage system provides 1C groups are used
one carbon groups in synthesis (Fig.12.20)
Do Conjugation Glycine conjugates with bile acids Bile salts are essential to form glycocholic acid (bile salt) for micelle formation
Alanine Pyruvate Transamination catalysed by Major glucogenic
Alanine amino transferase amino acid especially during starvation
Serine One carbon group Conversion of serine to glycine Major contributor of one
generates a one carbon group carbon groups
Do Ethanolamine Alpha decarboxylation of serine Used for phospholipids
synthesis
Do Phosphatidyl serine Serine as such is used Membrane phospholipid
Do Cysteine Carbon skeleton of cysteine Sulfur containing amino acid
Do Sphingosine Condenses with palmitoyl-CoA Alcohol present in
sphingolipids
Methionine Active methionine S-adenosylmethionine is formed Methylating agent for
reaction with ATP transmethylation
Do Polypeptides The initiator codon AUG codes Initiating amino acid in
for methionine translation
Do Polyamine Carbon skeleton is used for Regulation of gene
polyamine synthesis expression
Do Cysteine Degradation of methionine- Sulfur containing
transsulfuration amino acid
Cysteine SH groups in proteins Involved in reversible Active sites of
oxidation reduction enzymes, antioxidants
Do Glutathione Glutamic acid + glycine + cysteine Antioxidant
Do Taurine Oxidation and decarboxylation Conjugation of bile acid
Arginine Nitric oxide Nitric oxide synthase acts on arginine Signal molecule as
releasing NO potent vasodialator
Do Creatine Glycine + arginine + methionine High energy in muscle
Do Ornithine Removal of urea from arginine Used for polyamine
generates ornithine synthesis
Histidine Histamine Alpha decarboxylation Released by mast cells in
allergic reactions
Do Carnosine Dipeptide with beta alanine Found in skeletal muscle
Do Histidine in proteins Buffering action Hemoglobin and albumin
are rich in histidine
Do One carbon group Degradation of histidine Formimino group
generates FIGLU transferred to THFA
Glutamic acid Glutamine Ammonia is added by Ammonia fixation by brain
glutamine synthetase and nontoxic transport form of ammonia
Do Alphaketoglutaric acid Transmaination Member of TCA cycle
Do GABA (gamma Alpha decarboxylation Inhibitory
aminobutyric acid) neurotransmitter
Glutamine Purines, pyrimidines Amide group contributes N atoms Nucleic acid synthesis
Do Ammonia Glutaminase releases ammonia Used for excreting H ions
in the renal tubular cell as ammonium ions
Aspartic acid Amino group Used for synthesis of urea directly Detoxification of ammonia in urea cycle Do Purine, pyrimidine Pyrimidine and purine ring Nucleic acid synthesis
synthesis use C and N atoms of aspartate
Do Asparagine Ammonia fixation Amino acid which can
donate the amide group
Do Oxaloacetate Transamination by AST Starting molecule of TCA
cycle; gluconeogenic
Tyrosine Dopamine, Alpha decarboxylation, hydroxylation Alpha and beta
Norepinephrine, and methylation adrenergic activity;
Epinephrine Dopamine in brain
Do Thyroid hormones Iodination and coupling Stimulators of
T4 and T3 metabolism and growth
Do Melanin Oxidation and polymerization Sunscreen pigment
Tryptophan Serotonin Alpha decarboxylation Vasopressor amine
and hydroxylation mood regulation
Do Melatonin Acetylated serotonin Sleep wake cycles
Do NAD Major pathway Coenzyme for
dehydrogenases
Contd....
• Essential pentosuria (see Fig.7.2) • Fructose intolerance (see Fig.7.3) • Galactosemia (see Figs 7.4 and 7.5).
Fig. 12.20: One-carbon generation and utilization
A QUICK LOOK
• Pepsin, trypsin and chymotrypsin are the important protein hydrolysing enzymes in gastrointestinal tract.
• Amino acids are transaminated with a keto acid to produce another amino acid.
• Glutamic acid is deaminated to produce alpha keto glutaric acid and ammonia.
• Ammonia in brain is trapped by the glutamic acid to produce glutamine.
• Ammonia is finally excreted as urea. Urea is synthesized in the urea cycle.
• Normally urea level in blood is 20-40 mg/dl. It is increased in renal diseases.
• Glycine is used to synthesize serine, choline, creatine, creatinine, purine ring, heme, glutathione, bile salts.
• Glycine is also used for conjugation and detoxification reactions.
• Met hionine i s act iv at ed to S-adenosine methionine, which is used for transmethylation reactions.
• Methionine and cysteine m etabolism s are interconnected.
• Glutathione is synthesized by using cysteine. • Hom ocyst inur ia is due to the absence of
cystathionine synthase
• Phenylalanine is converted to tyrosine by phenyl- alanine hydroxylase.
• When this enzyme is absent, it leads to phenyl- ketonuria, an inborn error of metabolism. There will be severe mental retardation in this condition. • Important specialized products from tyrosine are
melanin, epinephrine and thyroxine.
• Deficiency of homogentisic acid oxidase leads to a condition called alkaptonuria, where homogentisic acid is excreted in urine, leading to black urine. • Absence of tyrosinase will lead to albinism. • Substances produced from tryptophan are alanine
(glucogenic), acetoacetyl-CoA (ketogenic), niacin, NAD+, serotonin, melatonin.
• One-carbon (1C) groups play a pivotal role in donating carbon atoms for synthesis of different types of compounds.
Total blood volume is about 4.5 to 5 liters in adult human being.
i. The defibrinated plasma is called serum, which lacks coagulation factors including prothrombin and fibrinogen.
ii. Total protein content of normal plasma is 6 to 8 g/100 ml.
iii. The plasma proteins consist of albumin (3.5 to 5 g/dl), globulins (2.5–3.5 g/dl) and fibrinogen (200–400 mg/dl). The albumin: globulin ratio is usually between 1.2:1 to 1.5:1. iv. Almost all plasma proteins, except immuno-
globulins are synthesized in liver.
ELECTROPHORESIS
In clinical laboratory, electrophoresis is employed regularly for separation of serum proteins. The term electrophoresis refers to the movement of charged particles through an electrolyte when subjected to an electric field. The details are given in Chapter 29. Abnormal electrophoretic patterns are shown in Fig. 13.1. The normal pattern is shown in the upper part of Fig. 13.1. and in Fig. 13.2.
CHAPTER AT A GLANCE
The reader will be able to answer questions on the following topics:
1. Electrophoresis of plasma proteins 2. Albumin, globulins, clinical significance 3. Transport proteins in blood
4. Acute phase proteins in blood 5. Ceruloplasmin 6. Clotting factors 7. Structure of immunoglobulins 8. Immunoglobulins G, M, A, D and E 9. Multiple myeloma 10. Bence-Jones Proteinuria
Fig. 13.1: Serum electrophoretic patterns Normal Values and Interpretations
i. In agar gel electrophoresis, normal serum is separated into 5 bands. Albumin, alpha-1- globulin, alpha-2-globulin, beta-globulin, and gamma globulin.
ii. Albumin has the maximum and gamma globulin has the minimum mobility in the electrical field.
Abnormal Patterns in Clinical Diseases
Various abnormalities can be identified in the electrophoretic pattern (Fig. 13.1).
13
1. Chronic infections: The gamma globulins are