BCM 2 Exam 2 Study guide final

What is the coenzyme involved in transaminase reactions?

Pyridoxal phosphate (PLP), the coenzyme form of vitamin B6.

What is the underlying role of PLP in transamination?

PLP acts as an intermediate carrier of amino groups at the active site of aminotransferases. Its aminated form is pyridoxamine phosphate (PMP).

What is the overall mechanism of a PLP-dependent transamination?

Amino acid + α-ketoglutarate ⇌ α-keto acid + glutamate. PLP accepts the amino group from the amino acid to become PMP, then PMP transfers that amino group to α-ketoglutarate, regenerating PLP.

What other reactions can PLP facilitate besides transamination?

Racemization and decarboxylation. All aminotransferases use PLP as a prosthetic group. Ch18 Candas Lecture (1)

What is the function of N-acetylglutamate?

N-acetylglutamate is the essential allosteric activator of carbamoyl phosphate synthetase I (CPS I).

How does N-acetylglutamate regulate the urea cycle?

It activates CPS I, the enzyme catalyzing the first committed step of the urea cycle, thereby increasing urea-cycle flux.

How is N-acetylglutamate produced and how does it regulate the urea cycle?

Glutamate + acetyl-CoA → N-acetylglutamate, catalyzed by N-acetylglutamate synthase. Arginine activates N-acetylglutamate synthase → ↑ N-acetylglutamate → activation of CPS I → ↑ urea-cycle flux.

What determines steady-state N-acetylglutamate levels in mammals?

Glutamate, acetyl-CoA, and arginine. Arginine activates N-acetylglutamate synthase and therefore indirectly activates the urea cycle. Chapter 18 textbook(1)

What processes are associated with the glucose-alanine cycle?

Muscle exports nitrogen and pyruvate as alanine to the liver; the liver disposes of the nitrogen as urea and returns the carbon as glucose.

What is the purpose of the glucose-alanine cycle?

It safely transports amino nitrogen from skeletal muscle to the liver while allowing the pyruvate carbon skeleton to be recycled into glucose.

What is the pathway of the glucose-alanine cycle?

Muscle: amino acids → glutamate; glutamate + pyruvate ⇌ α-ketoglutarate + alanine via alanine aminotransferase → alanine enters blood → liver: alanine + α-ketoglutarate ⇌ pyruvate + glutamate → glutamate releases NH4+ for urea synthesis; pyruvate → gluconeogenesis → glucose → blood → muscle.

Which two major metabolic processes are coupled by the glucose-alanine cycle?

Amino acid catabolism/nitrogen disposal and gluconeogenesis. Ch18 Candas Lecture (1)

What is the function of glutamate dehydrogenase in amino acid metabolism?

It reversibly converts glutamate to α-ketoglutarate and NH4+, linking amino-group metabolism to the citric acid cycle.

Why is glutamate dehydrogenase important for nitrogen disposal?

Transamination collects amino groups in glutamate, and GDH can release glutamate's amino group as NH4+ in liver mitochondria for urea synthesis.

What reaction is catalyzed by glutamate dehydrogenase?

Glutamate + NAD(P)+ + H2O ⇌ α-ketoglutarate + NH4+ + NAD(P)H + H+. GDH operates in the mitochondrial matrix and can use NAD+ or NADP+.

How is glutamate dehydrogenase regulated?

ADP positively modulates GDH, whereas GTP negatively modulates it. The α-ketoglutarate produced can enter the citric acid cycle or contribute to glucose synthesis. Ch18 Candas Lecture (1)

How is the energy demand of the urea cycle compensated?

Fumarate produced by the urea cycle enters the citric acid cycle, where its conversion ultimately generates NADH that can produce ATP.

Why is the energetic cost of the urea cycle lower than its ATP consumption alone suggests?

The aspartate-argininosuccinate shunt links the urea and citric acid cycles, allowing fumarate-derived NADH production to recover some energy.

How does the aspartate-argininosuccinate shunt compensate for urea-cycle energy use?

Argininosuccinate → arginine + fumarate → fumarate → malate → oxaloacetate. Malate → oxaloacetate generates NADH, whose oxidation can generate ATP; oxaloacetate can undergo transamination to regenerate aspartate.

How much energy does the urea cycle consume directly?

3 ATP molecules are consumed, but 4 high-energy phosphate bonds are used because one ATP is converted to AMP + PPi.

What compounds are excreted for the elimination of nitrogen in mammals?

Primarily urea; mammals can also excrete ammonium (NH4+), with other nitrogenous compounds contributing to nitrogen excretion.

Why do mammals primarily convert ammonia to urea?

Free ammonia is toxic, so ureotelic mammals detoxify amino nitrogen by converting it into the relatively nontoxic compound urea.

What is the general route for nitrogen excretion in mammals?

Amino acids → amino groups collected as glutamate/glutamine/alanine → liver → NH4+ → carbamoyl phosphate → urea cycle → urea → blood → kidneys → urine.

How do the major nitrogenous waste strategies differ among animals?

Ammonotelic animals excrete ammonia, ureotelic animals such as mammals excrete urea, and uricotelic animals excrete uric acid. Water availability is a major determinant. Ch18 Candas Lecture (1)

What is phenylketonuria (PKU)?

PKU is an inherited defect in conversion of phenylalanine to tyrosine, usually caused by phenylalanine hydroxylase deficiency.

What metabolic reaction is defective in classical phenylketonuria?

Phenylalanine → tyrosine is impaired because phenylalanine hydroxylase is deficient.

What is the normal phenylalanine hydroxylase reaction?

Phenylalanine + O2 + tetrahydrobiopterin (BH4) → tyrosine + H2O + dihydrobiopterin, catalyzed by phenylalanine hydroxylase; BH4 must subsequently be regenerated.

Why does phenylalanine accumulate in PKU?

Loss of phenylalanine hydroxylase activity prevents normal conversion of phenylalanine to tyrosine, causing phenylalanine and alternative metabolites to accumulate. Chapter 18 textbook(1)

How does the urea cycle support the Krebs cycle?

The urea cycle produces fumarate, which can enter the citric acid cycle through conversion to malate and oxaloacetate.

What is the metabolic connection between the urea cycle and the citric acid cycle?

The aspartate-argininosuccinate shunt connects the cycles through fumarate, malate, oxaloacetate, and aspartate.

Trace the connection between the urea cycle and Krebs cycle.

Argininosuccinate → arginine + fumarate → fumarate → malate → oxaloacetate → aspartate; aspartate reenters the urea cycle by combining with citrulline → argininosuccinate.

What useful products arise from the fumarate generated by the urea cycle?

Fumarate supplies a citric acid cycle intermediate and can generate NADH during malate → oxaloacetate.

Which compound directly donates a nitrogen atom for urea formation during the urea cycle?

Aspartate directly donates the second nitrogen of urea.

Where do the two nitrogen atoms of urea originate?

One nitrogen comes from free NH4+ and the second comes from aspartate.

How do the two nitrogens enter the urea cycle?

NH4+ → carbamoyl phosphate via CPS I → citrulline; aspartate then combines with citrulline → argininosuccinate. The two nitrogens are ultimately retained in urea.

At what step does aspartate donate its nitrogen to the urea cycle?

Citrulline + aspartate + ATP → argininosuccinate + AMP + PPi, catalyzed by argininosuccinate synthetase.

What is the metabolic defect in maple syrup urine disease?

Deficiency of the branched-chain α-keto acid dehydrogenase complex, impairing degradation of leucine, isoleucine, and valine.

Why does branched-chain α-keto acid dehydrogenase deficiency cause maple syrup urine disease?

The branched-chain amino acids are transaminated, but their resulting α-keto acids cannot undergo normal oxidative decarboxylation.

Where does the defective step occur in branched-chain amino acid catabolism in MSUD?

Leucine/isoleucine/valine → corresponding branched-chain α-keto acids by transamination → ✕ branched-chain α-keto acid dehydrogenase complex → downstream acyl-CoA derivatives.

Which three amino acids accumulate or are improperly degraded in maple syrup urine disease?

Leucine, isoleucine, and valine, the branched-chain amino acids. Chapter 18 textbook(1)

Where does urea synthesis take place in mammals?

In the liver, with the first two urea-cycle reactions in mitochondria and the remaining reactions in the cytosol.

Why does the urea cycle span two cellular compartments?

Carbamoyl phosphate and citrulline are produced in the mitochondrial matrix, after which citrulline is transported to the cytosol for the remaining reactions.

What is the compartmental organization of the urea cycle?

Mitochondria: NH4+ + HCO3− → carbamoyl phosphate → citrulline. Citrulline exits to cytosol. Cytosol: citrulline → argininosuccinate → arginine → urea + ornithine. Ornithine returns to mitochondria.

Which organ is specialized for converting excess amino nitrogen into urea?

The liver, particularly hepatocytes.

Catabolism of which amino acids yields pyruvate?

Alanine, cysteine, glycine, serine, threonine, and tryptophan can yield pyruvate.

Why are amino acids that yield pyruvate considered glucogenic?

Pyruvate can be converted to oxaloacetate and used for gluconeogenesis, allowing their carbon skeletons to contribute to glucose synthesis.

What is the general glucogenic pathway for amino acids that yield pyruvate?

Amino acid → pyruvate → oxaloacetate via pyruvate carboxylase + ATP + biotin → phosphoenolpyruvate → gluconeogenesis → glucose.

Are leucine and lysine able to produce pyruvate for gluconeogenesis?

No. Leucine and lysine are exclusively ketogenic and cannot contribute net carbon to gluconeogenesis.

In amino acid catabolism, what is the first reaction and cofactor for many amino acids?

Transamination, using pyridoxal phosphate (PLP).

What happens during the initial transamination step of amino acid catabolism?

The α-amino group is transferred from an amino acid to α-ketoglutarate, producing glutamate and the corresponding α-keto acid.

What is the general transamination reaction?

L-amino acid + α-ketoglutarate ⇌ α-keto acid + L-glutamate, catalyzed by an aminotransferase with PLP as the cofactor.

Why is glutamate central to amino acid catabolism?

Transamination funnels amino groups from many different amino acids into glutamate, which can subsequently release NH4+ through glutamate dehydrogenase. Chapter 18 textbook(1)

Which amino acid transports amino groups from muscle to the liver in a nontoxic form?

Alanine.

Why is alanine suited for transporting muscle nitrogen?

Muscle transfers amino groups to pyruvate to form alanine, allowing both nitrogen and the pyruvate carbon skeleton to travel safely to the liver.

How is alanine formed and used in the glucose-alanine cycle?

Muscle: glutamate + pyruvate ⇌ α-ketoglutarate + alanine via ALT → blood → liver → alanine + α-ketoglutarate ⇌ pyruvate + glutamate → NH4+ → urea; pyruvate → glucose.

What happens to the carbon skeleton of alanine after it reaches the liver?

It becomes pyruvate, which is used for gluconeogenesis; the resulting glucose can return to skeletal muscle. Ch18 Candas Lecture (1)

What is the function of tetrahydrofolate and its derivatives in metabolism?

Tetrahydrofolate (THF) carries and transfers one-carbon units in several oxidation states.

What types of groups are transferred by tetrahydrofolate derivatives?

One-carbon units, carried primarily at the N5 and/or N10 positions of tetrahydrofolate.

How does tetrahydrofolate participate in one-carbon metabolism?

One-carbon units enter the THF pool → are interconverted among THF derivatives such as N5,N10-methylene-THF and N5-methyl-THF → donated to biosynthetic reactions including nucleotide and methionine metabolism.

Why must tetrahydrofolate be regenerated after certain reactions?

THF is required repeatedly as a one-carbon carrier, so oxidized folate derivatives must be returned to the tetrahydrofolate state for continued one-carbon metabolism. Chapter 22 textbook(1)

Which enzyme is critical in activating protein-digesting zymogens in the small intestine?

Trypsin is the central activating protease; enteropeptidase initiates the cascade by converting trypsinogen to trypsin.

Why is trypsin central to pancreatic zymogen activation?

Once formed, trypsin activates additional trypsinogen as well as chymotrypsinogen, procarboxypeptidases, and proelastase.

What is the zymogen activation cascade in the small intestine?

Enteropeptidase: trypsinogen → trypsin → additional trypsinogen → trypsin; trypsin also activates chymotrypsinogen, procarboxypeptidases, and proelastase.

Why are pancreatic proteases synthesized as zymogens?

Inactive precursors protect the pancreas from self-digestion; pancreatic trypsin inhibitor provides additional protection. Chapter 18 textbook(1)

What substrate is used to synthesize methionine by methionine synthase?

Homocysteine is methylated to form methionine.

What does methionine synthase accomplish?

It transfers a methyl group to homocysteine, regenerating methionine.

What is the methionine synthase reaction?

Homocysteine + N5-methyl-THF → methionine + THF, catalyzed by methionine synthase with vitamin B12 participating in methyl transfer.

Why are folate and vitamin B12 metabolism connected to methionine synthesis?

Methionine synthase transfers a methyl group originating from N5-methyl-THF through a B12-dependent mechanism to homocysteine.

How many ATP are used in urea formation?

3 ATP molecules are consumed, corresponding to 4 high-energy phosphate bonds.

Why does the urea cycle use four high-energy phosphate bonds despite consuming only three ATP?

CPS I uses 2 ATP → 2 ADP, while argininosuccinate synthetase uses 1 ATP → AMP + PPi, equivalent to two high-energy phosphate bonds.

Where is ATP consumed during the urea cycle?

CPS I: NH4+ + HCO3− + 2 ATP → carbamoyl phosphate. Argininosuccinate synthetase: citrulline + aspartate + ATP → argininosuccinate + AMP + PPi.

What is the energetic accounting for one urea molecule?

3 ATP molecules are directly consumed, but 4 phosphoanhydride bonds are expended. Some energy is recovered through fumarate-linked NADH production.

Which two amino acids are exclusively ketogenic?

Leucine and lysine.

What does exclusively ketogenic mean?

Their carbon skeletons yield acetyl-CoA and/or acetoacetate rather than net gluconeogenic precursors, so they cannot produce net glucose.

What is the metabolic fate of exclusively ketogenic amino acids?

Leucine/lysine → ketogenic products such as acetyl-CoA or acetoacetate → ketone-body/lipid metabolism, rather than net gluconeogenesis.

Which amino acids cannot contribute to gluconeogenesis?

Leucine and lysine. All other amino acids have at least some glucogenic potential. Ch18 Candas Lecture (1)

What coenzyme is required for all transamination reactions?

Pyridoxal phosphate (PLP), derived from vitamin B6.

Why is PLP required for transamination?

PLP reversibly accepts an amino group to become pyridoxamine phosphate and then donates that amino group to an α-keto acid.

What are the two functional forms involved in PLP-dependent transamination?

PLP (aldehyde form) accepts an amino group → PMP (aminated form); PMP donates the amino group → PLP is regenerated.

How is PLP associated with an aminotransferase active site?

PLP is a prosthetic group of all aminotransferases and carries amino groups at the active site. Ch18 Candas Lecture (1)

What signals stimulate secretion of gastrin and secretin?

Dietary protein entering the stomach stimulates gastrin; low pH in the duodenum/small intestine stimulates secretin.

What is the physiological distinction between gastrin and secretin signaling?

Gastrin responds to food/protein in the stomach, whereas secretin responds to acidic gastric contents reaching the duodenum.

What are the downstream responses to gastrin and secretin?

Dietary protein → gastrin → parietal cells secrete HCl + chief cells secrete pepsinogen. Acidic chyme enters duodenum → secretin → pancreas secretes bicarbonate + water → gastric acid is neutralized and intestinal pH approaches optimal digestive pH.

What is the purpose of secretin-stimulated bicarbonate secretion?

It neutralizes gastric acid in the small intestine and maintains an appropriate pH for digestion. Ch18 Candas Lecture (1)

Metabolism of which amino acid is associated with serotonin production?

Tryptophan.

What is the relationship between tryptophan and serotonin?

Tryptophan is the amino acid precursor of serotonin (5-hydroxytryptamine).

What is the pathway from tryptophan to serotonin?

Tryptophan → 5-hydroxytryptophan → serotonin (5-hydroxytryptamine). Tryptophan hydroxylase uses tetrahydrobiopterin (BH4) in the hydroxylation step.

What important cofactor is shared by aromatic amino acid hydroxylases?

Tetrahydrobiopterin (BH4) is required by phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. Ch18 Candas Lecture (1)(3)

Which amino acid is used to make phosphocreatine?

Creatine is synthesized from glycine, arginine, and methionine, then phosphorylated to phosphocreatine.

What is the metabolic role of phosphocreatine?

Phosphocreatine acts as a rapidly mobilizable reserve of high-energy phosphoryl groups, particularly in muscle.

What is the pathway for creatine and phosphocreatine biosynthesis?

Arginine + glycine → guanidinoacetate → methylation using a methionine-derived methyl donor → creatine; creatine + ATP ⇌ phosphocreatine + ADP, catalyzed by creatine kinase.

Which three amino acids contribute to creatine biosynthesis?

Glycine, arginine, and methionine. Chapter 22 textbook(1)

Which compound is required for the synthesis of methionine?

N5-methyltetrahydrofolate provides the methyl group required to convert homocysteine to methionine.

Why is N5-methyltetrahydrofolate required for methionine synthesis?

It supplies the one-carbon methyl group transferred to homocysteine by methionine synthase.

What is the folate-dependent pathway for methionine synthesis?

N5-methyl-THF + homocysteine → THF + methionine, catalyzed by methionine synthase through a vitamin B12-dependent methyl-transfer mechanism.

What vitamin is closely linked to folate during methionine synthesis?

Vitamin B12, which participates in the methionine synthase reaction.

What are the bile pigments?

Biliverdin and bilirubin are major bile pigments produced during heme degradation.

Where do bile pigments come from?

They arise from degradation of the heme porphyrin ring.

What is the basic pathway for bile-pigment production?

Heme → biliverdin → bilirubin. Heme oxygenase opens the heme ring to produce biliverdin; biliverdin is subsequently reduced to bilirubin.

What is bilirubin's relationship to heme metabolism?

Bilirubin is a product of heme degradation and is handled by the liver for eventual elimination in bile.