Harpers

GLUCONEOGENESIS & CONTROL OF THE BLOOD GLUCOSE / 155D. GLUCOSE 1-PHOSPHATE & GLYCOGENThe breakdown of glycogen to glucose 1-phosphate iscatalyzed by phosphorylase. Glycogen synthesis involvesa different pathway via uridine diphosphate glucoseand glycogen synthase (Figure 18–1).The relationships between gluconeogenesis and theglycolytic pathway are shown in Figure 19–1. Aftertransamination or deamination, glucogenic amino acidsyield either pyruvate or intermediates of the citric acidcycle. Therefore, the reactions described above can accountfor the conversion of both glucogenic aminoacids and lactate to glucose or glycogen. Propionate is amajor source of glucose in ruminants and enters gluconeogenesisvia the citric acid cycle. Propionate is esterifiedwith CoA, then propionyl-CoA, is carboxylated toD-methylmalonyl-CoA, catalyzed by propionyl-CoAcarboxylase, a biotin-dependent enzyme (Figure 19–2).Methylmalonyl-CoA racemase catalyzes the conversionof D-methylmalonyl-CoA to L-methylmalonyl-CoA, which then undergoes isomerization to succinyl-CoA catalyzed by methylmalonyl-CoA isomerase.This enzyme requires vitamin B 12 as a coenzyme, anddeficiency of this vitamin results in the excretion ofmethylmalonate (methylmalonic aciduria).C 15 and C 17 fatty acids are found particularly in thelipids of ruminants. Dietary odd-carbon fatty acidsupon oxidation yield propionate (Chapter 22), which isa substrate for gluconeogenesis in human liver.Glycerol is released from adipose tissue as a result oflipolysis, and only tissues such as liver and kidney thatpossess glycerol kinase, which catalyzes the conversionof glycerol to glycerol 3-phosphate, can utilize it. Glycerol3-phosphate may be oxidized to dihydroxyacetonephosphate by NAD + catalyzed by glycerol-3-phosphatedehydrogenase.SINCE GLYCOLYSIS & GLUCONEOGENESISSHARE THE SAME PATHWAY BUT INOPPOSITE DIRECTIONS, THEY MUSTBE REGULATED RECIPROCALLYChanges in the availability of substrates are responsiblefor most changes in metabolism either directly or indirectlyacting via changes in hormone secretion. Threemechanisms are responsible for regulating the activityof enzymes in carbohydrate metabolism: (1) changes inthe rate of enzyme synthesis, (2) covalent modificationby reversible phosphorylation, and (3) allosteric effects.Induction & Repression of Key EnzymeSynthesis Requires Several HoursThe changes in enzyme activity in the liver that occurunder various metabolic conditions are listed in Table19–1. The enzymes involved catalyze nonequilibrium(physiologically irreversible) reactions. The effects aregenerally reinforced because the activity of the enzymescatalyzing the changes in the opposite direction variesreciprocally (Figure 19–1). The enzymes involved inthe utilization of glucose (ie, those of glycolysis and lipogenesis)all become more active when there is a superfluityof glucose, and under these conditions the enzymesresponsible for gluconeogenesis all have lowactivity. The secretion of insulin, in response to increasedblood glucose, enhances the synthesis of the keyCH 2PropionateCoAATPSHMg 2+ACYL-CoASYNTHETASEAMP + PPiCH 3CO 2 + H 2 OPROPIONYL-CoACARBOXYLASECH 2BiotinCO S CoAATP ADP + PiPropionyl-CoAHCH 3CCOCOO –SCoACH 3S CoACOO – CH 2METHYLMALONYL-CoARACEMASEIntermediatesof citric acid cycleFigure 19–2.COO –CH 2COMetabolism of propionate.Succinyl-CoAMETHYLMALONYL-CoA ISOMERASEB 12 coenzyme– OOCCH 3CCOHSD-Methylmalonyl-CoAL-Methylmalonyl-CoACoA