Metabolic Pathways and Thiamine Deficiency

Metabolic Pathways for Major Nutrient Conversion to Usable Energy

• Major nutrients are carbohydrates, fats, and proteins
• These nutrients are broken down into usable energy through metabolic pathways

Inadequate Diet: Thiamine Deficiency

• Thiamine deficiency is more common in famine areas or alcohol-dependent populations in developed nations
• Several syndromes are recognized:
  • Wernicke-Korsakoff Syndrome: Symptoms include confusion, abnormal eye movements, and ataxia (lack of muscle coordination)
  • Beri-Beri: Symptoms include cardiac failure and peripheral neuropathy (damage to peripheral nerves)
• Symptoms of severe B1 deficiencies include vomiting, tachycardia (fast heart rate), heart failure, convulsions, muscle weakness and atrophy (dry beriberi), and edema (wet beriberi) as well as progressive paralysis

Thiamine-Dependent Enzymes

• These enzymes are vital for energy generation
• Key enzymes include pyruvate dehydrogenase, α-ketoglutarate dehydrogenase (part of the citric acid cycle), and transketolase (involved in ribose synthesis from glucose)

How Serious is Thiamine Deficiency?

• Thiamine deficiency mainly affects individuals with malnutrition or alcohol dependence
• In those with alcohol dependence, alcohol displaces other nutrients, interfering with thiamine absorption and accelerating thiamine turnover
• This can result in brain damage (mammillary bodies and hypothalamus)
• Subclinical cases of Wernicke's encephalopathy are often missed, delaying treatment

Many Water-Soluble Vitamins as Coenzymes

• Several vitamins act as coenzymes
  • B1 (thiamine): Thiamine pyrophosphate (TPP)
  • B2 (riboflavin): Flavin nucleotides (FADH2)
  • B3 (niacin): Nicotinamide nucleotides (NADH)
  • B5 (pantothenic acid): Coenzyme A
  • Biotin: Coenzyme for pyruvate carboxylase, and acetyl CoA carboxylase
  • B6 (pyridoxine): Transamination reactions
  • C (ascorbic acid): Synthesis of hydroxyproline in collagen

Major Nutrient Metabolism: Overview

• Fats are broken down into fatty acids and glycerol which enter the metabolic pathway
• Polysaccharides (complex carbohydrates) are broken down into glucose and other sugars entering the metabolic pathway
• Proteins are broken down into amino acids, which also enter the metabolic pathway at various stages
• All pathways ultimately connect to the citric acid cycle
• Oxidative phosphorylation then generates ATP

Naturally Occurring Fatty Acids

• Fatty acids are typically composed of an even number of carbon atoms
• They can be saturated (no double bonds) or unsaturated (with one or more double bonds). Unsaturated fats can be either mono-unsaturated (MUFA) or poly-unsaturated (PUFA).
• Unsaturated double bonds can be cis or trans

Comparing Cis and Trans Fatty Acids

• The majority of fatty acids in nature are in the cis configuration
• Cis double bonds create kinks in the fatty acid chain which lower the melting point, making them liquid at body temperature
• Trans fatty acids have a straight structure which results in higher melting points

Trans Fatty Acids

• Small amounts of trans fatty acids occur naturally in animal fats
• However, large amounts of trans fats are created by the partial hydrogenation of vegetable oils
• Trans fats raise LDL (low-density lipoprotein) cholesterol levels and lower HDL (high-density lipoprotein) cholesterol levels

Fatty Acid Metabolism

• Triacylglycerols are broken into glycerol and three fatty acid chains
• Glycerol enters glycolysis as a substrate for the formation of glucose
• Fatty acids are oxidized and two carbon molecules break off as acetyl-CoA

Fatty Acid Oxidation

• Fatty acid energy is extracted primarily by β-oxidation
• Each cycle in β-oxidation produces one acetyl-CoA, FADH2, and NADH from a two-carbon unit in the fatty acid chain. Four steps per cycle are required
• The Overall reaction for complete β-oxidation of palmitate releases 8 Acetyl CoA, 7 FADH2, and 7 NADH

Fatty Acid Oxidation and the Citric Acid Cycle

• Fatty acid oxidation and the citric acid cycle are linked by the generation of acetyl CoA
• The citric acid cycle generates NADH and FADH2
• Both pathways generate NADH and FADH2 from acetyl-CoA which can generate 2.5 ATP for each NADH and 1.5 ATP for each FADH2

Metabolic Fates of Excessive Acetyl CoA

• In a normal condition, excessive acetyl CoA produced after a meal is utilized to form fat and transported to adipose tissue via lipoproteins
• In pathological conditions (e.g., diabetes mellitus or fasting), excess acetyl CoA is converted into ketone bodies used by other organs as energy sources

Amino Acid Metabolism

• Proteins are digested into amino acids, which are absorbed into blood and extracellular fluid
• Surplus proteins can serve as metabolic fuel sources, as do carbohydrates and fats
• Excess nitrogen is removed, producing carbon skeletons, and ammonia. The carbon skeletons then enter the metabolic pathways.

Protein Breakdown and Catabolism of Amino Acids

• Amino acids undergo transamination to yield keto acids
• Keto acids then enter either glycolysis or the Krebs cycle and, via intermediates, are oxidized to generate ATP
• Essential amino acids are used to build proteins in the body

Overview: Degradation of Amino Acid Carbon Skeletons

• Amino acids are categorized as glucogenic or ketogenic based on their metabolic fate, determining their contribution to glucose or ketone production
• Amino acid metabolism is part of the central pathway of energy metabolism

Amino Acid Metabolism: Overview

• Dietary proteins are broken down into amino acids
• The nitrogen atom of amino acids is removed by deamination to generate ammonia as a byproduct
• The carbon skeletons of amino acids can be used to produce metabolic intermediates that feed into the citric acid cycle, or glucose
• The nitrogen group is processed further and excreted as urea

Summary

• ATP is used as a readily available energy source
• ATP generation involves the metabolism of dietary carbohydrates and fats
• Glucose, other sugars, fatty acids, and amino acids undergo specific catabolic pathways
• These pathways generate intermediates such as acetyl CoA which enter the citric acid cycle and result in ATP production
• Many important vitamins act as coenzymes for these biochemical reactions