Metabolism of Lipids, Nucleotides, Amino acids, and Hydrocarbons LIPIDS | HSCI 4607, Study notes of Health sciences

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Bacterial Physiology:HSCI 4607/

CH: 9 :Metabolism of Lipids,

Nucleotides, Aminoacids, and Hydrocarbons

LIPIDS:

Introduction: Structurally lipids are heterogeneous group of substances. Their distinguished properties include:

• They are made up of fatty acids
• Highly soluble in nonpolar solvents such as ethanol, methanol, acetone, chloroform and so on.
• Relatively insoluble in water. Lipids are important components of bacterial and eukaryotic cell membranes. The major lipid present in these membrane is phospholipid which is also called phophoglycerides. Phosphoglycerides are made up of fatty acids esterified to glycerol phosphates. Archaea also have phospholipids but they have different chemical structure and mode of synthesis.

Fatty Acid Degradation: -Oxidation:Many bacteria when they grow on long chain fatty acids, they oxidize fatty acids to acetyl-CoA via pathway called -Oxidation. Reaction 1: In the first step the fatty acid is converted to Acyl-CoA derrivative in a reaction catalyzed by Acyl-CoA synthetase. This takes place in two steps: First the ATP molecule loses PP and gets attached to the fatty acid at carboxyl end to form Acyl adenylate (Acyl-AMP). In a second step the AMP molecule is replaced by CoASH to form Fatty Acyl-CoA. Reaction 2: In this step Acyl-CoA dehydrogenase oxidizes and forms double bond between the C2 and C3. Reaction 3: The double bond is hydrated by 3-hydroxyacyl- CoA hydrolase during this step. Reaction 4: The hydroxyl group is oxidized in this step to form keto group by L-3-hydroxyacyl-CoA dehydrogenase.

Fate of Acetyl-CoA: Acetyl-CoA thus released is metabolyzed to CO2 in aerobic bacteria via citric acid cycle or it can be utilized via glyoxylate cycle. The other product Fatty acyl CoA enters into another cycle of -oxidation to generate another molecule of Acetyl-CoA. Thus if the fatty acid is made up of even number of carbons, it is completely metabolized to Acetyl-CoA while if it is odd number chain then the last fragment of propionyl-CoA is metabolized by variety of oxidative path ways. One example is: Propionyl-CoA >> Acrylyl-CoA >> Lactyl-CoA >> Pyruvate

Fatty Acid Synthesis: Fatty acid biosynthetic pathways differ from -oxidation pathway in several ways:

1. The reductant is NADPH, instead of NADH in -oxidation.
2. It requires CO2 and proceeds via carboxylated derivative of Acetyl-CoA called Malonyl-CoA.
3. The acyl carrier carrier is ACP (Acyl carrier protein) instead of CoA in -oxidation. ACP is a small protein having MW of 10,000 in E.coli. In eukaryotes the synthesis takes place in the cytosol while the degradation takes place in matrix of mitochondria. In bacteria both the reactions take place in the cytoplasm.

Reaction 5: -ketoacyl-ACP is then reduced to the hydroxy derivative by an NADPH-dependent -ketoacyl-ACP reductase to 3- hydroxyl acyl-ACP, which is in reaction 6, dehydrated by dehydrase to yield unsaturated acyl-ACP derivative. Reaction 7: The unsaturated acyl-ACP is then reduced by enoyl-ACP reductase to saturated Acyl-ACP. The ACP chain is elongated by repetition of series of identical reactions initiated by attack of Malonyl-ACP on acyl-ACP chain to remove ACP. The biosynthetic pathway is possibly regulated through feed back inhibition. When acyl-ACP chain is completed, the acyl portion is immediately transferred to membrane phospholipids by the enzyme ‘Glycerol phosphate acyltransferase reactions’. For the synthesis of unsaturated fatty acids the Acyl-ACP or Acyl-CoA is dehydrated or desaturated by specific enzymes depending upon the type of bacteria and aerobic or anaerobic conditions.

Phospholipid Biosynthesis

Archaeal Lipids: There are notable differences between archaeal and bacterial lipids as follows:

1. Archaeal lipids contain long-chain alcohols called isopranyl alcohols instead of fatty acids.
2. The linkage to glycerol is via an ether bond instead of an ester bond.

STRUCTURES OF NUCLEOTIDES:

The Synthesis of Pyrimidine Nucleotides: The pyrimidine ring of nucleotide is made from, Aspartate, Ammonia, and Carbon dioxide. The phosphoribosyl pyrophosphate donates the ribose phosphate moiety to the nucleotides. This pathway leads to the synthesis of Uridine triphosphate which serves as a precursor for the formation of cytidine triphosphate through ammonification. Methylation of UTP at 5th C forms thymidine triphosphate. Thus UTP serves as precursor for the synthesis of the other pyrimidines.

Biosynthesis of Purine Nucleotides: The precursors for purine synthesis are glutamine, aspartate, glycine, CO2, and a C1 unit at the oxidation state of formic acid. The amino groups are donated by glutamine and aspartate while glycine, CO2 and formic acid donate carbon atoms. Enzymatic reactions: Step1: The synthesis of purine nucleotides begins with ribose phosphate which is derived from PRPP. In the first step the amino group donated by glutamine is attached to PRPP to form 5-phospho- ribosylamine. Thus amino group displaces PP group at C1 and the reaction is driven by the energy released by the hydrolysis of PP. Step 2: In this step glycine is added to the amino group to form 5-phosphoribosyl-glycinamide at the cost of ATP hydrolysis. The formyl group is added from formyl-THF which is followed by addition of another amino group from glutamine. This step also consumes one ATP. The resulting 5-phosphoribosyl-N-formylglycineamidine cyclizes to form imidazole ring with the hydrolysis of ATP molecule.

Purine synthesis….. The imidazole ring serves as precursor and additional carbon atoms are contributed by CO2, aspartate and formyl-THF to ultimately form ‘Inosinic acid’. Inosinic acid is the precursor to all the purine nucleotides. Adenine nucleotide: Adenine nucleotide is formed by substitution of the carbonyl oxygen at C6 of IMP with an amino group from aspartate.This reaction requires GTP. Guanidine nucleotide:This is formed by oxidation of IMP at C2 followed by an amination of C2. Glutamine is the donor of amino group. The THF:The tetra hydrofolic acid (THF) derivatives which are synthesized from vitamin B folic acid, are important single carbon donor during purine biosynthesis. The deoxyribonucleotides: They are synthesized by reductive dehydration of ribonucleoside diphosphates, catalyzed by ‘Ribonucleoside diphosphate reductase’ which uses protein ‘thioredoxin’ as electron donor coupled with NADPH.