Campbell University MSBS 501 Biochemistry & Cell Biology 2024 PDF

Copyright Notice and Agreement Class document distributed for the exclusive use of students in the CUSOM, MSBS class. Student access to and use of class materials are conditioned on agreement with the terms and conditions set out below. Any student who does not agree to them is prohibited fr...

Copyright Notice and Agreement Class document distributed for the exclusive use of students in the CUSOM, MSBS class. Student access to and use of class materials are conditioned on agreement with the terms and conditions set out below. Any student who does not agree to them is prohibited from accessing or making any use of such recordings. Any student accessing class materials (1) acknowledges the faculty members’ intellectual property rights in lectures and class materials and that distribution violates the CUSOM Copyright Policy; (2) recognizes the privacy rights of fellow students who speak in class; (3) accepts that distributing, posting, or uploading class materials to students or any other third party not authorized to receive them or to those outside CUSOM is an Honor Code violation; and (4) agrees that all class materials are to be  Synthesis and Degradation of Amino Acids Jackson T. Sparks, PhD – Smith Hall 437 [email protected] -- 910-814-4949 MSBS 501 2024 Learning Objectives – Amino Acid Synthesis and Degradation Define the following terms as they relate to amino acids: glucogenic, ketogenic, essential, nonessential, conditionally essential For the following diseases, name the enzymatic defect, what the biochemical consequences are (what accumulates?), what the basic clinical symptoms are, and what, if any, treatments are used and the logic behind the treatments: phenylketonuria (classic and BH4 deficient), Maple Syrup Urine Disease, albinism, homocystinuria, and alkaptonuria Name an additional use for each of the following amino acids: methionine, arginine, glutamine, histidine, tryptophan, tyrosine, alanine  Amino Acid Synthesis and Degradation Notice in the figure, that the carbon skeletons of amino acids can shuttle into pathways we have already seen. The backbones can be converted into intermediates of the TCA cycle, pyruvate, or acetyl CoA or acetoacetate. Depending on where the skeletons can funnel into known pathways, they are given the designations of glucogenic and/or ketogenic.  Amino Acid Synthesis and Degradation Glucogenic – an amino acid that can be converted into pyruvate or an intermediate of the TCA cycle. The term comes from the fact that these amino acids are substrates for gluconeogenesis, therefore their breakdown can give rise to a net increase in glucose formation in the liver.  Amino Acid Synthesis and Degradation Glucogenic – an amino acid that can be converted into pyruvate or an intermediate of the TCA cycle. The term comes from the fact that these amino acids are substrates for gluconeogenesis, therefore their breakdown can give rise to a net increase in glucose formation in the liver.  Amino Acid Synthesis and Degradation Ketogenic – amino acids that can be converted into acetoacetate (a ketone body) or a precursor (acetyl-CoA or acetoacetyl-CoA) to acetoacetate.  Amino Acid Synthesis and Degradation Ketogenic – amino acids that can be converted into acetoacetate (a ketone body) or a precursor (acetyl-CoA or acetoacetyl-CoA) to acetoacetate.  Amino Acid Synthesis and Degradation Nonessential – these are amino acids that can be synthesized by biochemical pathways in human cells. Essential – these are amino acids that can not be synthesized by humans, or that cannot be synthesized in sufficient quantities to meet the metabolic demands of the body.  Amino Acid Synthesis and Degradation Another term that you may see is conditionally essential, which is an amino acid that would normally be considered nonessential becoming “essential” to meet an increased demand (an example from the text is glutamine and arginine supplementation in trauma patients).  Amino Acid Metabolism Rather than go into a detailed discussion of the synthesis and breakdown of all of the amino acids, we are going to focus on those that are the most “medically relevant”. In particular, we will look closely at some amino acid disorders, and the role of certain vitamins in metabolism.  Amino Acid Metabolism Phenylketonuria (PKU) Classic PKU is caused by a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine.  Amino Acid Metabolism Phenylketonuria (PKU) Classic PKU is caused by a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. This causes levels of phenyalanine in tissues, blood, and urine to rise dramatically, as well as the presence of some metabolites of phenylalanine that are not normally present (see figure). These metabolites give the urine a characteristic musty odor which is where PKU got its name (phenylpyruvate is a phenylketone).  Amino Acid Metabolism PKU can also be caused by a deficiency of tetrahydrobiopterin due to a deficiency of one of the enzymes required to synthesize this essential cofactor. However, this cofactor is also required for the conversion of certain amino acids to neurotransmitters, such as tyrosine to catecholamines and tryptophan to serotonin. In these cases, treatment must also attempt to replace the tetrahydrobiopterin or the neurotransmitters themselves.  Amino Acid Metabolism Maple Syrup Urine Disease (MSUD) A deficiency in branched-chain alpha- keto acid dehydrogenase,  Amino Acid Metabolism Maple Syrup Urine Disease (MSUD) A deficiency in branched-chain alpha-keto acid dehydrogenase, which prevents the catabolism of the branched chain amino acids (Isoleucine, Leucine, and Valine (I Love Vermont Maple Syrup)). The presence of these amino acids in the urine give it its characteristic smell. A newborn will be very ill and die within a few weeks if not diagnosed and treated (so more severe than PKU), and as with PKU a major effect can also be intellectual disability (if treatment is insufficient).  Amino Acid Metabolism Maple Syrup Urine Disease (MSUD) Another point about branched-chain alpha-keto acid dehydrogenase, is it is the fourth enzyme that requires thiamine as a cofactor (the others were pyruvate dehydrogenase and alpha- ketoglutarate dehydrogenase (or complexes) from the TCA cycle and transketolase from the HMP pathway). There is a non-classical form of MSUD that is responsive to high doses of thiamine.  Amino Acid Metabolism Albinism A defect in a number of enzymes that are involved in the conversion of tyrosine to melanin will cause albinism.  Amino Acid Metabolism Albinism A defect in a number of enzymes that are involved in the conversion of tyrosine to melanin will cause albinism. The most severe form is Complete Albinism in which the deficiency is in the enzyme tyrosinase, and results in a complete lack of pigment. An increased risk of skin cancer is a big concern of these patients.  Amino Acid Metabolism Homocystinuria Defect in cystathionine beta- synthase.  Amino Acid Metabolism Homocystinuria Defect in cystathionine beta-synthase. Symptoms – displacement of the lens of the eye, skeletal abnormalities, neurological defects (intellectual disability), and early and severe atherosclerosis. Homocysteine is another compound that when present in elevated levels, can react with LDLs to cause them to be recognized as “damaged” leading to early atherosclerosis. Treatment will include limiting methionine and supplementing with B6, B12, and folate.  Amino Acid Metabolism Homocystinuria Defect in cystathionine beta- synthase. Treatment will include limiting methionine and supplementing with B6, B12, and folate. Amino Acid Metabolism Homocystinuria Folate – An earlier figure shows where B12 and Folate come into play in metabolism of methionine and homocysteine. Elevated levels of homocysteine and/or low levels of folate are associated with neural tube defects in a fetus, and pregnant women are advised to supplement their diet with folate because of this. Amino Acid Metabolism Homocystinuria Additionally, beyond the rare genetic condition of homocystinuria, mild elevations of homocysteine are seen in about 7% of the population (probably due to normal variations in metabolic enzymes). In these patients, supplementation with B12, B6, and folate can reduce homocysteine levels.  Amino Acid Metabolism Alkaptonuria deficiency of homogentisate oxidase (HO).  Amino Acid Metabolism Alkaptonuria Deficiency of homogentisate oxidase (HO). Relatively benign condition Patient’s urine will turn black upon standing for a period of time, reflective of oxidation of homogentisic acid in the urine. Black pigmentation (ochronosis) of cartilage and collagenous tissue. Only serious problem is arthritis, which can be severe. Diets low in protein, especially phenylalanine or tyrosine, can help with symptoms.  Amino Acid Metabolism Additional Amino Acid facts: Methionine – source of methyl groups in metabolism Arginine – Member of urea cycle, precursor of nitric oxide Glutamine – Transport of ammonia, precursor for nucleotide biosynthesis Histidine – precursor of histamine Tryptophan – precursor of serotonin Tyrosine – precursor for catecholamines Alanine – transport of ammonia (muscle)